Fidelity of program implementation under real-world conditions is a critical issue in the dissemination of evidence-based school substance use prevention curricula. Program effects are diminished when programs are implemented with poor fidelity. We assessed five domains of fidelity—adherence, exposure (dosage), quality of delivery, participant responsiveness and program differentiation (lack of contamination from other programs)—in a subset of respondents (N = 342) from a national random sample of public schools with middle school grades (N = 1721). Respondents taught 1 of 10 evidence-based universal substance use prevention programs as their primary program during the 2004–05 school year. Their responses to survey questions about their recent implementation practices indicated that fidelity was high for quality of delivery and participant responsiveness, low for program differentiation and modest for adherence and exposure—the two core domains of fidelity. Results suggest the need for continued emphasis on fidelity in program materials, trainings and on-going technical support. Particular attention should be paid to supporting use of interactive delivery strategies.