Although relapse prevention (RP) has become a widely adopted cognitive-behavioral treatment intervention for alcohol, smoking, and other substance use, outcome studies have yielded an inconsistent picture of the efficacy of this approach or conditions for maximal effectiveness. A meta-analysis was performed to evaluate the overall effectiveness of RP and the extent to which certain variables may relate to treatment outcome. Twenty-six published and unpublished studies with 70 hypothesis tests representing a sample of 9,504 participants were included in the analysis. Results indicated that RP was generally effective, particularly for alcohol problems. Additionally, outcome was moderated by several variables. Specifically, RP was most effective when applied to alcohol or polysubstance use disorders, combined with the adjunctive use of medication, and when evaluated immediately following treatment using uncontrolled pre-post tests.