BACKGROUND: Administration of sulfadoxine-pyrimethamine at times of vaccination-intermittent preventive treatment in infants (IPTi)-is a promising strategy to prevent malaria. However, rising resistance to this combination is a concern. We investigated a shortacting and longacting antimalarial drug as alternative regimens for IPTi. METHODS: We undertook a double-blind, placebo-controlled trial of IPTi in an area of high resistance to sulfadoxine-pyrimethamine at sites of moderate (n=1280 infants enrolled) and low (n=1139) intensity of malaria transmission in Tanzania. Infants aged 8-16 weeks were randomly assigned in blocks of 16 to sulfadoxine (250 mg) plus pyrimethamine (12.5 mg; n=319 in moderate-transmission and 283 in low-transmission sites), chlorproguanil (15 mg) plus dapsone (18.75 mg; n=317 and 285), mefloquine (125 mg; n=320 and 284), or placebo (n=320 and 284), given at the second and third immunisations for diphtheria, pertussis, and tetanus, and for measles. Research team and child were masked to treatment. Recruitment was stopped early at the low-transmission site because of low malaria incidence. The primary endpoint was protective efficacy against all episodes of clinical malaria at 2-11 months of age. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00158574. FINDINGS: All randomly assigned infants were analysed. At the moderate-transmission site, mefloquine had a protective efficacy of 38.1% (95% CI 11.8-56.5, p=0.008) against clinical malaria in infants aged 2-11 months, but neither sulfadoxine-pyrimethamine (-6.7%, -45.9 to 22.0) nor chlorproguanil-dapsone (10.8%, -24.6 to 36.1) had a protective effect. No regimen had any protective efficacy against anaemia or hospital admission. Mefloquine caused vomiting in 141 of 1731 (8%) doses given on day 1 (odds ratio vs placebo 5.50, 95% CI 3.56-8.46). More infants died in the chlorproguanil-dapsone and mefloquine groups (18 and 15, respectively) than in the sulfadoxine-pyrimethamine or placebo groups (eight deaths per group; p=0.05 for difference between chlorproguanil-dapsone and placebo). INTERPRETATION: IPTi with a longacting, efficacious drug such as mefloquine can reduce episodes of malaria in infants in a moderate-transmission setting. IPTi with sulfadoxine-pyrimethamine has no benefit in areas of very high resistance to this combination. The appropriateness of IPTi should be measured by the expected incidence of malaria and the efficacy, tolerability, and safety of the drug. FUNDING: IPTi Consortium and the Gates Malaria Partnership.