Aims: The aim of this study was to establish prevalence estimates of problem drug use, defined as opiate and/or crack cocaine use by persons aged 15 to 64 years, for England and for each of the 149 administrative areas responsible for commissioning drug interventions. Methods: Indirect estimation techniques, the capture-recapture and multiple indicator methods, were used to obtain estimates. Information on problem drug users presenting to healthcare settings and/or recorded by the criminal justice system, and drug-related indicator data were used in the analyses. Findings: There were an estimated 332,090 problem drug users in England during 2005/06 (95% CI 324,546 to 346,345), equivalent to 9.97 (95% CI 9.74 to 10.40) problem drug users per thousand population aged 15 to 64 years. Prevalence varied by geographic region and age group: the highest rates were observed in London and for those aged 25 to 34 years. Conclusions: This study has produced estimates of the prevalence of problem drug use in England that are more robust, more precise, and suggest a higher prevalence than previous studies. The estimates provide a basis on which to formulate policy, plan services, and measure service performance.