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Background No data on once-daily dosing of nucleoside analogues in African children currently exist. We compared the pharmacokinetics (PK) of once- versus twice-daily lamivudine and abacavir treatment using the World Health Organization recommended weight band dosing of scored adult tablets.Methods HIV type-1 (HIV-1)-infected Ugandan children aged 3–12 years receiving antiretroviral therapy that included lamivudine and abacavir twice daily (total 150+300 mg, 225+450 mg and 225/300+600 mg daily for 12–<20, 20–<25 and =25 kg, respectively) were enrolled in a crossover study. Plasma PK sampling (at 0, 1, 2, 4, 6, 8 and 12 h after observed morning intake) was performed for the twice-daily regimen at steady-state. Children were then switched to once-daily treatment with PK sampling repeated 4 weeks later (with an additional 24 h sample). Acceptability questionnaires were completed at both time points. Daily area under the curve (AUC0–24) and maximum concentrations (Cmax) were compared by geometric mean ratios (GMRs).Results A total of 41 HIV-1-infected children (median age of 7 years) and n=23, n=14 and n=4 in 12–<20, 20–<25 and =25 kg weight bands, respectively, were enrolled. Mean AUC0–24was 13.0 and 12.0 mg•h/l for once- and twice-daily lamivudine (GMR 1.09, 90% confidence intervals [CI] 0.98–1.20) and 15.3 and 15.6 mg•h/l for once- and twice-daily abacavir (GMR 0.98, 90% CI 0.89–1.08), respectively, with no difference in 3–6 versus 7–12 year olds. Cmaxwas 76% (lamivudine) and 64% (abacavir) higher on once-daily regimens. For both children and caregivers, once-daily dosing of lamivudine plus abacavir was highly acceptable and strongly preferred over twice-daily.Conclusions In children aged 3–12 years, AUC0–24of lamivudine and abacavir were bioequivalent on once-and twice-daily regimens. Once-daily dosing of abacavir and lamivudine could provide an alternative dosing strategy for HIV-1-infected children, with high acceptability and strong preference suggesting the potential for improved adherence.