ABSTRACT Aims This study compared the characteristics of intravenous (i.v.) and intranasal (i.n.) heroin users seeking methadone treatment, and their response to treatment. Participants A total of 319 heroin-dependent adults. Design Participants were assigned randomly to receive interim methadone treatment or to a waiting list control on a 3 : 2 basis. Analyses were conducted by dividing participants into two groups based on their route of heroin ingestion: i.v. or i.n. Setting A methadone clinic in Baltimore City, Maryland. Intervention Interim methadone treatment consisted of providing an adequate and stable dose of methadone, but no psychosocial services, to heroin-dependent adults for up to 120 days while they awaited an opening for comprehensive methadone treatment. Measures Addiction Severity Index, Texas Christian University AIDS Risk Assessment, a questionnaire on treatment entry and a urine drug test were collected at baseline and at entry into a comprehensive treatment program, or at 120 days after baseline assessment, whichever came first. Findings At baseline, over 60% of participants were i.n. users and had been for an average of over 12 years; i.v. users, compared to i.n. users, were more likely to have ever used cocaine, to have used cocaine in the past 30 days, to have more medical complications and to report more income generated from criminal behavior. Both i.v. and i.n. users reduced their self-reported days of heroin use, cocaine use and days of criminal activity in response to interim methadone treatment. Conclusions Despite differences in baseline characteristics, i.n. and i.v. heroin-dependent individuals did not differ in their response to interim methadone treatment.