PurposeTo examine time-varying associations between predictors of recent multiple sexual partners from middle adolescence through young adulthood. MethodsWe examined whether the odds of multiple partners in the past year were differentially predicted by substance use and depression over time, using data from a nationally representative longitudinal study (N = 11,963, 52.2% female, 18.3% African-American, 11.9% Hispanic, 3.5% Asian, 2.6% other race, M age at Wave I = 16.1 years, SD = 1.8). Data were analyzed using the time-varying effect model, which estimates associations between predictors and an outcome as a function of near-continuous time. ResultsThe proportion of participants having multiple partners increased over time, leveling off at around 30% after age 20. Significant positive associations between substance use and multiple partners were strongest early in adolescence and decreased sharply by around age 18. The significant positive association between depression and sexual behavior weakened with age, remaining significant in young adulthood for women but not men. ConclusionsThese findings suggest that factors associated with having multiple recent sexual partners change from middle adolescence through young adulthood. The time-varying effect model can be used to identify risk factors that are especially salient at different ages, thus identifying which age periods may hold the greatest promise for intervention.