Prior research suggests that high dispositional self-regulation leads to decreased levels of risky drinking and sexual behavior in adolescence and the early years of college. Self-regulation may be especially important when individuals have easy access to alcohol and freedom to pursue sexual opportunities. In the current 1-year longitudinal study, we followed a sample of N = 1,136 college students who had recently reached the legal age to purchase alcohol and enter bars and clubs to test whether self-regulation protected against heavy episodic drinking, alcohol-related problems, and unprotected sex. We tested main effects of self-regulation and interactions among self-regulation and established risk factors (e.g., sensation seeking) on risky drinking and sexual behavior. High self-regulation inversely predicted heavy episodic drinking, alcohol-related problems, and unprotected sex, even when taking into account gender and risk factors. Moreover, in predicting unprotected sex, we found three-way interactions among self-regulation, sensation seeking, and heavy episodic drinking. Self-regulation buffered against risk associated with heavy drinking but only among those low in sensation seeking. The protective effects of self-regulation for risky drinking and sexual behavior make it a promising target for intervention, with the caveat that self-regulation may be less protective among those who are more drawn to socially and emotionally rewarding stimuli.