To determine and compare risk factors for HIV infection among cisgender female sex workers (CFSWs) and transgender female sex workers (TFSWs).Baseline data from a cohort study (SAPPHIRE) of street-based CFSW and TFSW in Baltimore, MD.Women were queried about individual (eg, drug use), interpersonal (eg, sexual abuse), and structural (eg, housing) risk factors and questioned on their sex work risk environment. Women were tested for HIV/sexually transmitted infections. We used logistic regression to identify key risk factors for prevalent HIV in each population.We recruited 262 CFSW and 62 TFSW between 2016 and 2017. Compared with TFSW, CFSW were more likely to be white (66% vs. 0%), recently homeless (62% vs. 23%, P < 0.001), regularly gone to sleep hungry (54% vs. 16%, P < 0.001), and to inject drugs (71% vs. 4%, P < 0.001). HIV prevalence was 8 times greater in TFSW than in CFSW (40% vs. 5%, P < 0.001). All participants reported high rates of lifetime physical and sexual violence. Cocaine injection [adjusted odds ratio (aOR) = 3.65, 95% confidence interval (CI): 1.12 to 11.88], food insecurity (aOR = 1.92, 95% CI: 1.22 to 3.04), and >5 years in sex work (aOR = 5.40, 95% CI: 2.10 to 13.90) were independently associated with HIV among CFSW. Childhood sexual abuse (aOR = 4.56, 95% CI: 1.20 to 17.32), being in sex work due to lack of opportunities (aOR = 4.81, 95% CI: 1.29 to 17.90), and >5 years in sex work (aOR = 5.62, 95% CI: 1.44 to 21.85) were independently associated with HIV among TFSW.Although distinct, both populations share a history of extensive childhood abuse and later life structural vulnerability, which drive their engagement in street-based sex work and their HIV risk profiles.