The Multisite Opiate Substitution Treatment study evaluated whether adhering to clinical-trial-derived practice guidelines improves treatment outcomes of unselected opiate-dependent patients seen in everyday practice. Clinics that were relatively concordant (n = 4) or nonconcordant (n = 4) with guidelines concerning medication dose levels and psychosocial service provision were identified. Staff interviewed 256 patients at intake and 6-month follow-up regarding past month heroin use, criminal activities, and mental health. To represent real-world practice conditions, clinics provided care in accordance with their usual approach, and no patient exclusion criteria were employed. Patients in each type of clinic were similar at baseline, but by follow-up, heroin use and mental health outcomes were significantly better in guideline-concordant clinics than in guideline-discordant clinics. Notably, 60.6% of patients in concordant clinics had urinalysis-confirmed heroin abstinence versus only 40.0% in nonconcordant clinics. Following research-derived practice guidelines seems to increase opiate substitution treatment effectiveness for opiate-dependent patients in the real world.