BACKGROUND: Several microbicide candidates show activity against pathogens that cause sexually transmitted infections (STIs). This may increase a microbicide's impact on HIV in phase 3 trials. Modeling is used to estimate the degree to which a microbicide's STI efficacy contributes to the HIV effectiveness of a phase 3 microbicide trial. METHODS: An expression is derived and coupled with an STI model to estimate how much a microbicide's STI efficacy contributes to a trial's HIV effectiveness. The STI model estimates the decrease in STI prevalence that may occur in the trial's active gel arm for microbicides of different STI efficacy. Projections are produced for different STI cofactors and epidemiological settings. RESULTS: The model projects that if a microbicide is active against curable STIs with a combined prevalence of >or=10% among trial participants and the reduction in HIV incidence is <50%, then the STI activity could have substantially contributed to the trial's HIV effectiveness (>50% in some cases) if the per exposure multiplicative STI cofactor is 2.5 or greater. However, if the STI prevalence is <10% or the STI cofactor is <2.5 or if the reduction in HIV incidence is >50%, then the trial's HIV effectiveness will be mainly due to its direct HIV efficacy. CONCLUSIONS: In high STI settings, phase 3 trials documenting a moderate impact on HIV incidence may partially result from a gel's activity against curable STI. Care should be taken generalizing these trial results to other settings. This is less important for trials documenting large reductions in HIV incidence.