BACKGROUND: Truck drivers in sub-Saharan Africa are at high risk for both mental health disorders and sexually transmitted infections. We sought to determine the prevalence of depression among a sample of long-distance truck drivers seeking services at roadside wellness clinics in Kenya and explore the relationship between depression and sexual risk behavior. METHODS: We used data from an interviewer-administered questionnaire from 284 truck drivers in Kenya who participated in a randomized controlled trial evaluating whether offering oral HIV self-testing could increase HIV test uptake. Depression was categorized based on the Patient Health Questionnaire-9 score, with a score ≥10 indicative of probable major depressive disorder (MDD). Sexual risk behavior was operationalized as the number of condomless sex partners in the past 6 months. RESULTS: The mean participant age was 36.9 years, 83.0% were married, and 37.0% had a secondary school education or higher. Overall, 24% of participants had probable MDD, and 58.2% reported having one condomless sex partner in the past 6 months, whereas 27.3% reported having had two or more. In a multivariable Poisson regression model adjusted for demographic and other relevant variables, including number of sex partners, MDD was significantly associated with a greater number of condomless sex partners (adjusted prevalence ratio 1.63, 95% confidence interval [1.25-2.12], p < 0.001). General self-efficacy significantly mediated the association between MDD and number of condomless sex partners. CONCLUSIONS: The high prevalence of depression highlights the need to test the feasibility and acceptability of mental healthcare interventions for this population, possibly integrated with HIV prevention services. Future research is needed to better understand the association between depression and sexual risk behavior, as well as the role of self-efficacy.