BACKGROUND This study investigated the relationship between four suspected risk factors-affective dysregulation, conduct problems, depressive symptoms, and psychological distress-and incident nonmedical prescription analgesic (NPA) use among college students. METHODS The sample was derived from 929 college students from a large, mid-Atlantic university who completed the third annual College Life Study assessment (Y3) and were NPA use naïve at baseline (Y1). A series of logistic regression analyses were conducted to evaluate the predictors of incident NPA use by Y3. Separate models were developed to evaluate the association between the suspected risk factors and (a) NPA use relative to non-use of other drugs, including nonmedical use of other drug classes, (b) NPA use relative to other drug use, and (c) other drug use relative to non-use. All models included gender, parental education level, and race/ethnicity. RESULTS Affective dysregulation was significantly associated with becoming an incident NPA user relative to both drug users without NPA use as well as non-users, after statistically controlling for demographic characteristics and other factors. Conduct problems in early childhood were positively related to both incident NPA use and other drug use without NPA use relative to non-users, after statistically controlling for demographic characteristics and other factors. Depressive symptoms were associated with NPA incidence at the bivariate level only. CONCLUSIONS These findings extend previous research suggesting that NPA use might be related to deficits in regulating negative emotional states, and highlight possible markers for screening and intervention to prevent NPA use.