Genital herpes is a chronic, stigmatizing, sexually transmitted disease (STD), which is increasing despite efforts to control its spread. Depression is commonly reported among people diagnosed with genital herpes and differences in depression by gender have been reported. Therefore, the purpose of this study was to identify gender differences in the predictors of depression in young adults with genital herpes by secondary analyses of baseline data from a randomized clinical trial (RCT). For the RCT, young adults (193 females, 59 males) with genital herpes were recruited from newspaper advertisements. Participants completed questionnaires measuring illness burden, attitudes toward herpes, stress symptoms, mood states, depression, self-concealment, self-disclosure, substance use, and demographics. Univariate analyses and multiple regression techniques were used to identify variables predictive of depression in this sample. In women, increased anger, decreased vigor, increased confusion, a negative attitude toward herpes, self-concealment, and stress symptoms from genital herpes predicted more depression (R2 = 0.63). In men, increased depression was predicted by increased anger, a negative attitude toward herpes, and a decreased willingness to share personal information with a stranger (R2 = 0.51). Findings suggest that future psychoeducational interventions should address anger as a predictor of depression in this population. Gender-specific interventions need to be developed in order to assist young adults who are living with genital herpes.