Aims The present study examines the prevalence trends and college-level characteristics associated with the non-medical use of prescription drugs (i.e. amphetamines, opioids, sedatives, tranquilizers) and illicit drug use among US college students between 1993 and 2001. Design Data were collected from self-administered mail surveys, sent to independent cross-sectional samples of college students from a nationally representative sample of 119 colleges in 4 years between 1993 and 2001. Setting Nationally representative 4-year US colleges and universities in 1993, 1997, 1999 and 2001. Participants Representative samples of 15 282, 14 428, 13 953 and 10 904 randomly selected college students at these colleges in 1993, 1997, 1999 and 2001, respectively. Findings The results indicate that life-time and 12-month prevalence rates of non-medical use of prescription drugs (NMPD) increased between 1993 and 2001. Specific college-level characteristics were found to be correlated positively (marijuana use) and negatively (historically black college status and commuter status) with NMPD, consistently across the four cross-sectional samples. Significant between-college variation in terms of trajectories in the prevalence of NMPD over time was found in hierarchical linear models, and selected college-level characteristics were not found to explain all of the variation in the trajectories, suggesting the need for further investigation of what determines between-college variance in the prevalence trends. Conclusions The findings of the present study suggest that continued monitoring of NMPD and illicit drug use among college students is needed and collegiate substance prevention programs should include efforts to reduce these drug use behaviors.