Substance prevention programs proliferate throughout America's Schools. Since 1998, the US Department of Education (US DOE) has required that school-based programs funded with federal subsidies be subject to a four stage process to insure effectiveness. The current study applies multivariate Ordinary Least Squares (OLS) techniques to data from a nationally representative probability sample of 16,001 youths aged 12-17 to examine whether attendance to in-school primary prevention programs for substance use reduces tobacco, alcohol and marijuana use. The results indicate significant, but irrelevant reductions in the use of tobacco (r[superscript 2] = 0.54), alcohol (r[superscript 2] = 0.044) and marijuana r[superscript 2] = 0.030). Recommendations are made for review of school-based substance prevention programs to insure compliance to the US DOE guidelines, to terminate funding for programs that are not effective and for directions in future research. (Contains 6 tables and 2 footnotes.)