Women engaged in sex work (WESW) have an elevated risk of the human immunodeficiency virus (HIV) and sexually transmitted infections (STI). Estimates are three times higher than the general population. Understanding the predictors of HIV and STI among WESW is crucial in developing more focused HIV and STI prevention interventions among this population. The study examined the prevalence and predictors of HIV and STI among WESW in the Southern part of Uganda. Baseline data from the Kyaterekera study involving 542 WESW (ages 18-55) recruited from 19 HIV hotspots in the greater Masaka region in Uganda was utilized. HIV and STI prevalence was estimated using blood and vaginal fluid samples bioassay. Hierarchical regression models were used to determine the predictors of HIV and STI among WESW. Of the total sample, 41% (n = 220) were found to be HIV positive; and 10.5% (n = 57) tested positive for at least one of the three STI (Neisseria gonorrhoeae, Chlamydia trachomatis and Trichomonas vaginalis) regardless of their HIV status. Older age (b = 0.09, 95%CI = 0.06, 0.13, p≤0.001), lower levels of education (b = -0.79, 95%CI = -1.46, -0.11, p≤0.05), fewer numbers of children in the household (b = -0.18, 95%CI = -0.36, -0.01), p≤0.05), location (i.e., fishing village (b = 0.51, 95%CI = 0.16, 0.85, p≤0.01) or small town (b = -0.60, 95%CI = -0.92, -0.28, p≤0.001)), drug use (b = 0.58, 95%CI = 0.076, 1.08, p≤0.05) and financial self-efficacy (b = 0.05, 95%CI = -0.10, 0.00, p≤0.05), were associated with the risk of HIV infections among WESW. Domestic violence attitudes (b = -0.24, 95%CI = -0.42, -0.07, p≤0.01) and financial distress (b = -0.07, 95%CI = -0.14, -0.004, p≤0.05) were associated with the risk of STI infection among WESW. Study findings show a high prevalence of HIV among WESW compared to the general women population. Individual and family level, behavioural and economic factors were associated with increased HIV and STI infection among WESW. Therefore, there is a need for WESW focused HIV and STI risk reduction and economic empowerment interventions to reduce these burdens.