Although published research based on retrospective survey designs has established prescription drug misuse as a serious health issue for individuals and society, misuse behavior has not been investigated as it occurs in daily life and important relationships. To address this gap, young adult romantic couples were recruited from the community to participate in an experience sampling study. Participants were identified through phone screen procedures as having engaged in recent prescription drug misuse behavior. Participants (n = 46 couples) completed electronic diary reports throughout the day for 10 days, tapping momentary affect, sexual experiences, prescription drug misuse, and alcohol and other drug use. Dyadic multilevel modeling revealed a more consistent pattern of associations between prescription drug misuse and problematic affective and behavioral outcomes for female partners than male partners. Specifically, during epochs of females' prescription drug misuse, they experienced relatively higher levels of negative affect and sexual regret. Also, females who misused prescriptions more during the study period evidenced lower levels of sexual enjoyment and engaged in more unprotected sex, alcohol use, and heavy alcohol use in daily life. Males' in-the-moment prescription drug misuse was not associated with their concurrent outcomes, though males with relatively more misuse across the reporting period were more likely to engage in heavy drinking. Couples' time together emerged as a moderator of prescription drug misuse in daily life: Females who spent relatively more time with their partner across the study were less likely to engage in misuse, and proportion of time spent together moderated several of the momentary misuse-outcome linkages. This study supports the use of ecologically-valid sampling methods for characterizing young adults' prescription drug misuse in daily life and relationship contexts.