Antiretroviral-therapy rollout in resource-poor countries is often associated with limited, if any, HIV-RNA monitoring. The effect of variable monitoring on the emergence of resistance after therapy with commonly used drug combinations was assessed by systematic review of studies reporting resistance in patients infected with HIV with a CD4 count of fewer than 200 cells per muL treated with two nucleoside analogues (including a thymidine analogue) and a non-nucleoside reverse transcriptase inhibitor. 8376 patients from eight cohorts and two prospective studies were analysed. Resistance at virological failure to non-nucleoside reverse transcriptase inhibitors at 48 weeks was 88.3% (95% CI 82.2-92.9) in infrequently monitored patients, compared with 61.0% (48.9-72.2) in frequently monitored patients (p<0.001). Lamivudine resistance was 80.5% (72.9-86.8) and 40.3% (29.1-52.2) in infrequently and frequently monitored patients, respectively (p<0.001); the prevalence of at least one thymidine analogue mutation was 27.8% (21.2-35.2) and 12.1% (5.9-21.4), respectively (p<0.001). Genotypic resistance at 48 weeks to lamivudine, nucleoside reverse transcriptase inhibitors (thymidine analogue mutations), and non-nucleoside reverse transcriptase inhibitors appears substantially higher in less frequently monitored patients. This Review highlights the need for cheap point-of-care viral-load tests to identify early viral failures and limit the emergence of resistance.