OBJECTIVE: To examine whether the level of primary resistance to HIV drugs is increasing in the United Kingdom. DESIGN: Multicentre observational study. SETTING: All virology laboratories in the United Kingdom carrying out tests for HIV resistance as part of routine clinical care. PARTICIPANTS: 2357 people infected with HIV who were tested for resistance before receiving antiretroviral therapy. MAIN OUTCOME MEASURE: Prevalence of drug resistance on basis of the Stanford genotypic interpretation system. RESULTS: Over the study period (February 1996 to May 2003), 335 (14.2%, 95% confidence interval 12.8% to 15.7%) samples had mutations that conferred resistance to one or more antiretroviral drugs (9.3% high level resistance, 5.9% medium level resistance). The prevalence of primary resistance has increased markedly over time, although patterns are specific to drug class; the largest increase was for non-nucleoside reverse transcriptase inhibitors. In 2002-3, the prevalence of resistance to any antiretroviral drug to nucleoside or nucleotide reverse transcriptase inhibitors, to non-nucleoside reverse transcriptase inhibitors, or to protease inhibitors was 19.2% (15.7% to 23.2%), 12.4% (9.5% to 15.9%), 8.1% (5.8% to 11.1%), and 6.6% (4.4% to 9.3%), respectively. The risk of primary resistance was only weakly related to most demographic and clinical factors, including ethnicity and viral subtype. CONCLUSIONS: The United Kingdom has one of the highest reported rates of primary resistance to HIV drugs worldwide. Prevalence seems still to be increasing and is high in all demographic subgroups.