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New sex partners put adolescents at increased risk for sexually transmitted infections (STIs), even when these sex partners are nonoverlapping. Although the risk of partner change is well described, little is known about its antecedents. We prospectively examined associations between relationship characteristics, partner change, and subsequent STI during intervals of “serial monogamy.”As part of a longitudinal study, 332 adolescent women were interviewed and tested for gonorrhea, chlamydia, and trichomonas every 3 months for up to just over 6 years. Interviews covered partner-specific relationship characteristics and sexual behaviors. The quarterly interval, a 3-month period bracketed by interviews and STI testing, was the unit of analysis. We examined associations among relationship factors, partner change, and subsequent STI using a series of mixed regression models, controlling for age, STI at Time 1, and condom nonuse.Age, lower relationship quality, and lower levels of partner closeness to friends and family predicted partner change from Time 1 to Time 2. In turn, partner change was associated with acquisition of a new STI at Time 2. Although relationship factors did not exert a direct effect on STI at Time 2, they improved partner change—STI model fit. Similar patterns were seen with each organism.Relationship factors drive partner change, which in turn contributes to STI acquisition. STI prevention research may need to focus on the relationship antecedents to partner change, in addition to the partner change itself.