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Once-daily regimens of antiretroviral therapy are simpler than other regimens, but whether such regimens are associated with better adherence to treatment is controversial. We performed a meta-analysis of 11 randomized, controlled trials (total number of subjects, 3029), which revealed that the adherence rate was better with once-daily regimens (+2.9%; 95% confidence interval, 1.0%–4.8%; P<.003) than with twice-daily regimens. This modest effect was more pronounced at the time of treatment initiation and for regimens for which all medications were taken once per day.