Recognition of HIV-1 ssRNA by Toll-like receptor 7 induces the production of the pro-inflammatory cytokines that may contribute to the systemic immune activation associated with HIV-1 disease progression. Here, we describe a novel association between polymorphisms in interferon regulatory factor 7 (IRF7), a master regulator of interferon-α (IFN-α), and the ability of plasmacytoid dendritic cells to produce IFN-α in response to HIV-1. IRF7 polymorphisms may, therefore, affect the ability of individuals to respond to HIV-1 and modulate HIV-1 disease progression.