Public health agencies across the globe are working to mitigate the impact of the 2009 pandemic caused by swine-origin influenza A (H1N1) virus. Prior to the large-scale distribution of an effective vaccine, the primary modes of control have included careful surveillance, social distancing and hygiene measures, strategic school closures, other community measures, and the prudent use of antiviral medications to prevent infection (prophylaxis) or reduce the severity and duration of symptoms (treatment). Here, we use mathematical models to determine the optimal geo-temporal tactics for distributing the U.S. strategic national stockpile of antivirals for treatment of infected cases during the early stages of a pandemic, prior to the wide availability of vaccines.We present a versatile optimization method for efficiently searching large sets of public health intervention strategies, and apply it to evaluating tactics for distributing antiviral medications from the U.S. Strategic National Stockpile (SNS). We implemented the algorithm on a network model of H1N1 transmission within and among U.S. cities to project the epidemiological impacts of antiviral stockpile distribution schedules and priorities. The resulting optimized strategies critically depend on the rates of antiviral uptake and wastage (through misallocation or loss). And while a surprisingly simple pro rata distribution schedule is competitive with the optimized strategies across a wide range of uptake and wastage, other equally simple policies perform poorly.Even as vaccination campaigns get underway worldwide, antiviral medications continue to play a critical in reducing H1N1-associated morbidity and mortality. If efforts are made to increase the fraction of cases treated promptly with antivirals above current levels, our model suggests that optimal use of the antiviral component of the Strategic National Stockpile may appreciably slow the transmission of H1N1 during fall 2009, thereby improving the impact of targeted vaccination. A more aggressive optimized antiviral strategy of this type may prove critical to mitigating future flu pandemics, but may increase the risk of antiviral resistance.