Globally, transgender women have higher risk for HIV than the general population and men who have sex with men, but there is little data on this population in Vietnam. In 2015 we conducted a biological and behavioral survey of 205 transgender women in Ho Chi Minh City, Vietnam. Factors associated with HIV and syphilis infection were assessed through multivariable logistic regression models. Median age was 25 years (range 18-64). Overall prevalence was 18.0 % for HIV and 17.6 % for syphilis. Factors independently associated with HIV infection included risky alcohol use [adjusted Odds Ratio (aOR) 3.55, 95 % confidence interval (CI) 1.53-8.21], amphetamine stimulant use (aOR 2.90, 95 % CI 1.27-6.61), sex with male sex workers (aOR 4.73, 95 % CI 1.72-13.0), and history of sex with an adult before the age of 18 years (aOR 2.97, 95 % CI 1.06-8.34). Two factors associated with syphilis infection were HIV infection (aOR 2.37, 95 % CI 1.03-5.45) and condomless anal sex with casual partners (aOR 2.27, 95 % CI 1.03-5.00). In order to address the HIV and syphilis epidemics in Vietnamese transgender women, interventions are needed to make HIV and sexually transmitted infection screening and treatment more accessible.