ABSTRACT. Objective: The goal of this research was to evaluate economically three interventions designed to prevent substance use in general populations of adolescents, specifi cally focusing on the prevention of methamphetamine use and its subsequent benefi ts to employers. Method: In a randomized, controlled trial, three preventive interventions were delivered to 6th-or 7th-grade youth in 58 Iowa school districts, with 905 of these youth (449 girls) providing follow-up assessments as 12th graders. Intervention conditions included the family-focused Iowa Strengthening Families Program (ISFP), the school-based Life Skills Training (LST) program, and a combined condition of both the Strengthening Families Program: For Parents and Youth 10-14 (SFP10-14; an ISFP revision) plus LST (LST + SFP10-14). Analyses based on intervention costs, 12th-grade methamphetamine use rates, and methamphetamine-related employer costs yielded estimates of intervention cost, cost-effectiveness, benefi t-cost ratio, and net benefi t. Results: The ISFP lowered methamphetamine use by 3.9%, cost $25,385 to prevent each case, and had a benefi t-cost ratio of 3.84, yielding a net benefi t of $2,813 per youth. The LST program reduced methamphetamine use by 2.5%, required $5,122 per prevented case, and had a benefi t-cost ratio of 19.04, netting $2,273 per youth. The combined LST + SFP10-14 prevention condition lowered methamphetamine use rates by 1.8%, cost $62,697 to prevent each case, had a benefi t-cost ratio of 1.56, and netted $620 per youth. Findings were robust after varying a number of key parameters across a range of plausible values. Conclusions: Substance use prevention programming is economically feasible, particularly for effective interventions that have lower per person treatment delivery costs. (J. Stud. Alcohol Drugs, 72, 577-585, 2011)