OBJECTIVE To determine the prevalence, characteristics and virological outcomes of triple-class antiretroviral drug failure (TCF) and triple-class virological failure (TCVF) in HIV-infected patients attending an Australian high caseload primary care clinic. METHODS Cross-sectional observational study using a retrospective review of electronic medical records from 1007 patients with HIV attending Holdsworth House Medical Practice in Darlinghurst, Australia, between 2007 and 2008. TCF was defined as failure (virological, immunological, clinical, intolerance or other) of at least one drug in each of the three major classes of highly active antiretroviral therapy. RESULTS A total of 51 patients (5.1%) with TCF were identified. Of these patients, 31.4% had experienced virological failure of each of the three main drug classes. Eighty-eight percent of patients with TCF and 75% of patients with TCVF had achieved virological suppression (HIV RNA <400 copies mL(-1)). Total mean (s.d.) duration on antiretroviral therapy (ART) was 12.2 (3.3) years, with patients receiving an average of 18 antiretroviral drugs during this period. Reasons for treatment change included intolerance (88% of patients), virological failure (84%), immunological failure (24%) and poor adherence (20%). CONCLUSIONS The prevalence of TCF and TCVF in patients with long-term HIV infection and extensive antiretroviral experience is low in primary care sites. Despite experiencing failure to the three main classes of ART, successful virological outcomes are still achievable in the majority of such patients.