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<p>Abstract</p> <p>Background</p> <p>An artemisinin-based combination therapy, artesunate (AS) plus sulphadoxine-pyrimethamine (SP), was compared to SP monotherapy to provide evidence of further treatment options in southern Mozambique.</p> <p>Methods</p> <p>Between 2003 and 2005, 411 patients over one year and 10 kg with uncomplicated <it>Plasmodium falciparum </it>malaria were randomly allocated SP (25/1.25 mg per kg day 0) or AS/SP (as above plus 4 mg/kg artesunate days 0, 1 and 2). Allocation was concealed, but treatment was open-label except to microscopists. The primary objective was the relative risk of treatment failure, which was assessed using World Health Organization response definitions modified to a 42-day follow-up.</p> <p>Results</p> <p>Of the 411 subjects enrolled, 359 (87.3%) completed the follow up period (SP n = 175, AS/SP n = 184). A survival analysis including 408 subjects showed that the polymerase chain reaction-adjusted cure rates were 90.4% (95% confidence interval [CI] 84.9%–93.9%) and 98.0% (95% CI 94.8%–99.3%) for SP and AS/SP respectively. Multivariable analysis showed that treatment with AS/SP decreased the relative hazard of treatment failure by 80% compared to SP (hazard ratio [HR] 0.2; 95% CI 0.1–0.6) and age over seven years decreased the relative hazard of failure by 70% (HR 0.3; 95% CI 0.1–0.9), when compared to younger age. However, having a quintuple <it>dhfr</it>/<it>dhps </it>mutation increased the relative hazard of failure compared to fewer mutations (HR 3.2; 95% CI 1.3–7.5) and baseline axillary temperature increased the relative hazard of failure by 50% for each °C increase (HR 1.5; 95% CI 1.1–2.2).</p> <p>Conclusion</p> <p>While both treatments were efficacious, AS plus SP significantly decreased the relative hazard of treatment failure compared to SP monotherapy Artesunate plus sulphadoxine-pyrimethamine, but not sulphadoxine-pyrimethamine monotherapy, met the current WHO criteria of >95% efficacy for policy implementation.</p> <p>Trial registration</p> <p>NCT00203736 and NCT00203814</p>