The non-medical use of prescription drugs (NMUPD) among college students is escalating at an alarming rate. A limited number of studies have utilized a theoretical framework to influence this behavior. To utilize the reasoned-action approach theory to design and evaluate a web-based intervention to influence students' attitudes, perceived norms (PNs), perceived behavioral control (PBC) and intentions toward NMUPD. Using a two-group post-test only controlled trial, students were randomized to view either a general health website or a web-based intervention focused on NMUPD. The intervention was presented in multiple sections to address each component of the reasoned-action approach. Subsequently, respondents completed a web-survey. Independent t-tests were used to compare responses between the two groups. Of 391 respondents, 112 (28.9%) students indicated previous NMUPD. The intervention group had significantly (P = 0.04) more negative attitudes toward NMUPD. No significant differences were found in PNs (P = 0.11), PBC (P = 0.68) or intentions to NMUPD (P = 0.97). The intervention was successful in changing attitudes toward NMUPD. Targeting the intervention toward college students regardless of previous experiences of NMUPD might have led to insufficiency of the intervention to influence intentions. Additional research is needed to improve the intervention dissemination and utilization.