Objective: To examine the impact of nonmedical use of prescription drugs (NMUPD) during sexual activity on the frequency of condom use among a sample of college students. Participants: Students attending a large Midwestern University (N = 4284) during April 2015. Methods: Retrospective cross-sectional analysis of survey data using logistic regression. Results: Respondents and/or their sexual partners who engaged in NMUPD during sexual activity were significantly less likely to use condoms during 75% or more of past 12-month sexual encounters compared to respondents who had not engaged in lifetime and past 12-month NMUPD. Although not statistically significant, trends suggest that respondents who engaged in NMUPD during sexual activity may be less likely to use condoms than those who engaged in lifetime or past 12-month NMUPD but not during sexual activity. Conclusions: Findings suggest a need for specific strategies for reducing risk behaviors related to prescription drugs and sexual activity.