Severe malaria might have respiratory symptoms, which can progress to malaria-associated acute respiratory distress syndrome (MA-ARDS). Although mortality rate varies from 50 to 80% of cases, there is no specific treatment for MA-ARDS. In this context, the effects of acetylsalicylic acid (ASA), a non-steroidal anti-inflammatory widely used by population, including in endemic areas, on MA-ADRS remain unclear. Since combined artemisinin therapies are recommended by the World Health Organization, and dihydroartemisinin (DHA) have antimalarial and immunomodulatory proprieties, we hypothesized that ASA and combines therapy with DHA might prolong survival rate and modulate the inflammatory process in experimental MA-ARDS Aim: To evaluate the effects of acetylsalicylic acid (ASA) and combined therapy with dihydroarthemisinin (DHA) on experimental MA-ARDS. Methods: C57BL/6 mice were randomly divided in control (C) and infected (Pb) groups, intraperitoneally (ip) inoculated with uninfected erythrocytes or 104 Plasmodium berghei NK65 infected erythrocytes, respectively, and treated on day 8 orally with ASA (100mg/kg) or saline, and vehicle (DMSO) or DHA (3mg/kg), ip. Results: This is the first study that describes the functional impairment induced by PbNK65 on experimental MA-ARDS. For that, lung mechanics and pulmonary edema analysis were performed between days 6 to 10 post infection. PbNK65 led to increased lung static elastance (Est,L) on the 9th and 10th dpi (57±19cmH2O.ml-1; 71±4.8cmH2O.ml-1, respectively) increased resistive pressure (ΔP1,L) on the 10th dpi (0.9±0.3cmH2O.ml) and higher viscoelastic pressure (ΔP2,L) (0.9±0.1cmH2O.ml; 0.9±0.1cmH2O.ml and 1.1±0.3cmH2O.ml, respectively) from the 8th to 10th dpi, compared to C (Est,L= 35±3cmH2O.ml-1; ΔP1,L= 0.3±0.1cmH2O.ml; ΔP2,L=0.6±0.1cmH2O.ml) . PbNK65 infected mice showed a significant increase in lung edema on day 8 [5(5.1/4.7)] and 9 [4.8(5.1/4.7)] compared to control [4.4(4.6/4.2)]. Diffuse alveolar damage (DAD) score analysis have confirmed that both PbNK65 and Pb+DHA groups presented extravasation of fluid to alveolar space, alveolar septae thickening, edema and areas of microatelectasis compared to C. Lung hemorrhage was also observed in PbNK65 animals but not in Pb+DHA. Pb+DMSO presented thrombocytopenia (192±40 10³/ mm³) and leukocytosis (118±37 10³/mm³) on day 15. Seven days after DHA treatment, leukocytosis was reduced on Pb+DHA and Pb+DHA+ASA groups (11.5±7.8 10³/mm³ and 13±7.8 10³/mm³, respectively), but platelet count was maintained on Pb+DHA (376±151 10³/mm³) and ASA+DHA (312±139 10³/mm³). PbNK65 also led to increase on aspartate transaminase (AST) (619±112U/l) and decrease on serum albumin (2±0.1g/dL) and alkaline phosphatase (AP) (62±10U/l) levels compared to C group (AST= 108±47U/l; AP= 127±21U/l; Albumin= 2.5±0.1g/dL, respectively). Peripheral parasitemia on day 8 was directly correlated to increase on protein levels on bronchoalveolar lavage fluid (BALF) (r=0.72; p=0.0002). Pb+DMSO (5.8± 4.2mg/ml), Pb+ASA (4.4±3mg/ml) and Pb+DHA+ASA (3.7±2.5mg/ml) but not Pb+DHA (3.1±2.3mg/ml) showed higher protein levels on BAL compared to C (0.2± 0.09mg/ml). MCP-1 levels on BAL were higher in Pb+DMSO (300±146pg/ml) and Pb+DHA (221±189pg/ml) compared to C (4.9±2.8pg/ml) and decreased after and Pb+ASA (136±53pg/ml) or Pb+DHA+ASA (144±109pg/ml) treatment. Moreover, mononuclear cell count on lung tissue were higher on Pb+DMSO (41%) compared to C (30.6%) and decreased after Pb+DHA (35.1%), Pb+ASA (33%) and Pb+DHA+ASA (34%) treatment. On lung mechanics analysis, Pb+DMSO (72±10cmH2O.ml-1) and Pb+ASA (63±21cmH2O.ml-1) groups showed higher Est,L and DP1 (0.6±0.3cmH2O; 0.5±0.3cmH2O, respectively) than C (Est 42±6cmH2O.ml-1; DP1 0.4±0.1cmH2O); DP2 was higher on Pb+DMSO (1.1±0.3cmH2O) compared to C (0.7±0.1cmH2O). Pb+DHA (0.8±0.1cmH2O) and Pb+ASA (0.9±0.1cmH2O) groups presented reduced DP2 compared to Pb+DMSO. However, Pb+ASA (25%) presented similar survival rate to Pb+DMSO (27%). 78% of Pb+DHA+ASA and all Pb+DHA group survived until day 15. Conclusions: PbNK65 infection led to impairment on lung mechanics, lung edema and influx of macrophage and plasma proteins to the alveolar space. ASA and combined therapy with DHA reduced leukocytosis, MCP-1 levels on BAL and lung viscoelastic pressure, although did not decrease mortality associated to MA-ARDS.