Objectives To estimate prevalence and incidence of HIV and sexually transmitted infections (STI) and associated risk factors among young women working as sex workers (SWs) in Phnom Penh, Cambodia. Methods A prospective study of young (<29 years) women working as SWs in brothels, entertainment establishments, and freelance. Sociodemographics, sexual risk, and use of amphetamine-type stimulants (ATS) (“yama” and “crystal”) were assessed by self-report. HIV and STI (Chlamydia trachomatis and Neisseria gonorrhoeae) testing were conducted on blood and urine specimens, respectively. Results Baseline prevalences of HIV, C. trachomatis, and N. gonorrhoeae were 23%, 11.5%, and 7.8%, respectively. HIV incidence was 3.6 per 100 person-years (95% confidence interval [CI], 1.2%– 11.1%); STI incidence was 21.2 per 100 person-years (95% CI, 12.6%– 35.8%). At baseline, 26.5% reported recent ATS use. HIV infection was associated with freelance SW (adjusted odds ratio, 5.85; 95% CI, 1.59–21.58) and younger age of first sex (≤15 years; adjusted odds ratio, 3.06; 95% CI, 1.01–8.46). Incident STI was associated with duration (per year) of SW (adjusted hazard ratio, 1.1; 95% CI, 1.1–1.2) and recent yama use (adjusted hazard ratio, 3.9; 95% CI, 1.5–10.3). Conclusions HIV and STI infection rates were high among SWs working in various settings; freelancers had highest risk. ATS use was associated with incident STI. Venue of sex work and drug prevention should be considered in prevention programs.