Influenza virus infections represent a serious public health problem worldwide, due to the rapid emergence of drug resistance. One strategy to improve treatment efficacy is to combine drugs that act synergistically. Potentially useful drug combinations are typically identified through empirical testing using in vitro and animal models, but the complexity of the clinical situation warrants the use of more careful analysis and sophisticated approaches. To explore new approaches, we constructed a mechanistic model representing the interaction of antiviral drugs with the viral replication pathway and human immune responses. Simulation of combination therapy using oseltamivir and amantadine predicted significant therapeutic synergy only when immune response was included, in agreement with previous in vitro and in vivo studies using amantadine-resistant strains. Our model can be used to predict the optimal doses for combination therapy, and also raises questions about current drug evaluation methods that do not account for immune system interactions.