OBJECTIVES: To determine rates and causes of switching from first- to second-line antiretroviral treatment (ART) regimens in a large treatment-naive cohort (a South African community-based ART service) where a targeted adherence intervention was used to manage initial virological breakthrough. METHODS: ART-naive adults (n=929) commencing first-line non-nucleoside-based ART [according to WHO (2002) guidelines] between September 2002 and August 2005 were studied prospectively. Viral load (VL) and CD4+ T-cell counts were monitored every 4 months. All drug switches were recorded. Counsellor-driven adherence interventions were targeted to patients with a VL > 1000 copies/ml at any visit (virological breakthrough) and the VL measurement was repeated within 8 weeks. Two consecutive VL measurements > 1000 copies/ml was considered virological failure, triggering change to a second-line regimen. RESULTS: During 760 person-years of observation [median (IQR) 189 (85-441) days], 823 (89%) patients were retained on ART, 2% transferred elsewhere, 7% died and 3% were lost to follow-up. A total of 893 (96%) patients remained on first-line therapy and 16 (1.7%) switched to second-line due to hypersensitivity reactions (n=9) or lactic acidosis (n=7). A Kaplan-Meier estimate for switching to second-line due to toxicity was 3.0% at 32 months. Virological breakthrough occurred in 67 (7.2%) patients, but, following use of a targeted adherence intervention, virological failure was confirmed in just 20 (2.2%). Kaplan-Meier estimates at 32 months were 20% for virological breakthrough but only 5.6% for confirmed virological failure. CONCLUSION: Regimen switches were due to virological failure or toxicity. Although follow-up time was limited, over 95% of individuals remained on first-line ART using a combination of viral monitoring and a targeted adherence intervention.