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Abstract Background Economic vulnerability influences women engaged in commercial sex work (WESW) to further engage in sexual risk behaviors, as they often have multiple customers and engage in unprotected sex for financial gains. This study examined asset ownership’s direct and indirect impact on sexual risk-taking behaviors among WESW in Southern Uganda, a very vulnerable group of women at high risk for contracting HIV and other STIs. Methodology We used baseline data from the Kyaterekera study, an NIH-funded study among WESW aged 18–55 across 19 HIV hotspots in Southern Uganda. Structural equation modeling was used to examine the direct, indirect, and total effects of assets—defined as ownership of physical and financial resources—on sexual risk-taking behaviors among WESW. Results Results showed that asset ownership was associated with a decrease in depression (β = − 0.096 [95% CI − 0.191, − 0.001], p = 0.050) and increased access to medical care (β = 0.174 [95% CI 0.072, 0.275], p = 0.001).We also found that an increase in access to medical care was associated with decreased sexual risk-taking behaviors (β = − 0.107 [95% CI − 0.210, − 0.004], p = 0.041). We observed a specific indirect effect between assets and sexual risk-taking behaviors through access to medical care (β = − 0.019 [95% CI − 0.040, − 0.002], p = 0.05). Mediation contributed 31% of the total effects of asset ownership on sexual risk-taking behaviors. Conclusion To our knowledge, this is among the few studies to examine the impact of asset ownership on sexual risk-taking behaviors among WESW in Southern Uganda. Findings from this study indicate that increasing access to economic resources may reduce the risk of WESW engaging in unprotected sex for higher income, which limits the spread of HIV among this population. The results also indicate that asset ownership may allow women to access healthcare services.