Using signs, symptoms and serum methadone levels to guide evaluation, the authors treated 164 patients in a methadone maintenance program with doses of methadone exceeding 100 mg/d. The mean dose of these higher dose (HD) patients was 211 mg/d (range 110-780 mg/d). A comparison group (C) of 101 patients was randomly selected from the general clinic population (mean dose 65 mg/d). At intake the HD group reported $153/day of heroin use versus $87/day in the C group. The HD group had more patients whose opiate of choice was an oral pharmaceutical (30% versus 2% of the C group). Sixty-three percent of the HD group had comorbid Axis I psychiatric diagnoses compared to 32% of the C group. Response to psychopharmacologic treatment was enhanced by increased methadone dose in HD patients with "refractory" psychiatric disorders. Urine toxicologies described as "before" were collected prior to increase over 100 mg/d in the HD group or at the first routine urine toxicology collection of the calendar year for the C group. These results were compared to the most recent urine toxicologies for both groups ("after"). The percentage of toxicologies positive for illicit drugs in the HD group dropped from 87% "before" to 3% "after". The C group were 54% positive "before" and 37% positive "after". We conclude that doses of methadone in excess of 100 mg/d (range 110-780 mg/d in our sample of 164 patients) are not only safe but necessary to prevent illicit opiate use, stabilize psychiatric symptoms, and diminish abuse of alcohol and benzodiazepines in many patients.