OBJECTIVE: Despite increases in STIs among those over 40, little is known about the social context of STI transmission among people experiencing relationship transition in midlife, and few sexual health promotion initiatives are targeted at this group. This study sought to identify factors shaping STI risk perceptions and practices among midlife individuals either contemplating or having sex with new partners following the end of a long-term relationship. METHODS: Participants were purposively selected from respondents to Britain's third National Survey of Sexual Attitudes and Lifestyles, using three eligibility criteria: aged 40-59, reported experience of the end of a marital or cohabiting relationship with an opposite-sex partner in the past 5 years, and willingness to participate in a qualitative interview. Qualitative data were generated via face-to-face interviews with 10 women and 9 men and analysed inductively using thematic analysis, with themes then organised using a socioecological framework. RESULTS: Participants' accounts of new sexual partnerships in midlife indicate that STI risk perceptions and practices are shaped by factors operating at multiple levels across the socioecological arena (individual, partnership, peers and communities, societal). Constraints on, and resources for, the navigation of sexual safety include self-perceived STI risk rooted in past rather than present circumstances; legacies of mistrust within former relationships; intersecting gender-age dynamics in negotiation of risk prevention strategies with new partners; peers and younger relatives' influences on understandings of sexual risk and safety; postrelationship change in social networks that increase or mitigate vulnerability to sexual risk; age-related barriers to accessing condoms; and disconnection from safer sex messaging and services culturally coded as for the young. CONCLUSIONS: Improving sexual health among midlife adults requires age-sensitive interventions designed to address multilevel constraints, and harness positive influences, on the navigation of sexual safety at this stage of life.