This study describes the level of perceived harmfulness of nonmedical prescription stimulant and analgesic use in a sample of college students, and examines the prospective relationship between perceived harmfulness and subsequent nonmedical use. In addition, we explore whether the association between perceived harmfulness and nonmedical use varies by level of sensation-seeking. Personal interviews, including questions on sensation-seeking and drug use, were conducted with 1,253 first-year college students. Participants were then followed-up twice at 6-month intervals. Perceived harmfulness of nonmedical use of prescription drugs was assessed at 6 months via a web-based survey. At the 12-month follow-up interview, drug use was again assessed. Students who never had the opportunity to use prescription drugs nonmedically were excluded from all analyses. Results revealed that one in four students perceived a great risk of harm from occasional nonmedical use of prescription stimulants (25.2%) and analgesics (27.8%). As expected, low perceived harmfulness and high sensation-seeking were independently associated with increased risk of nonmedical use, holding constant demographic characteristics. The protective effect of high perceived harmfulness could be seen at all levels of sensation-seeking with one important exception: Among high sensation-seekers, perceived harmfulness was not related to nonmedical use of prescription analgesics. Perceived harmfulness appears to distinguish nonmedical users from non-users, given the opportunity to use. Increasing perceived harmfulness may be a viable prevention strategy for most students, but alternative approaches might need to be developed that are tailored to high sensation-seekers.