Postexposure prophylaxis (PEP) of influenza A virus (IAV)–infected mice with liponucleotides attenuates hypoxemia, bradycardia, and pulmonary edema without affecting viral replication. Effect of treating C57BL/6 mice infected with H1N1 influenza A/WSN/33 (10,000 plaque-forming units [pfu]/mouse) with sterile 0.9% saline (50 μl/mouse i.p.), 100 μg/mouse cytidine 5′-diphosphocholine (CDP-CHO) (in 50 μl sterile 0.9% saline i.p.), or 100 μg/mouse CDP-CHO + 10 μg/mouse CDP-DAG (in 50 μl sterile 0.9% saline i.p.) daily from 1 to 5 days post inoculation (d.p.i.) on (A) carotid SaO2 (percentage; n > 10/group), (B) heart rate (beats/min; n > 10/group), (C) lung water content (wet:dry weight;) at 6 d.p.i. (n ≥ 6/group), (D) BAL fluid protein at 6 d.p.i. (μg/ml; n = 5/group), and (E) lung homogenate viral titers (pfu × 107/g lung tissue; n = 5/group). All data were analyzed by ANOVA with a Tukey-Kramer multiple comparison post hoc test and are presented as mean ± SEM. #P < 0.001 versus mock-inoculated mice. §P < 0.001 versus saline-treated, IAV-infected mice. ‡P < 0.005 and ¶P < 0.001 versus CDP-CHO–treated, IAV-infected mice. DAG = diacylglycerol; SaO2 = arterial oxygen saturation.