Objective:To assess the causal prophylactic activity (activity against the pre‐erythrocytic liver stage) of a daily regimen of doxycycline combined with low dose primaquine against malaria in Australian Defence Force personnel deployed to Papua New Guinea (PNG).Participants and setting: A 53‐strong Australian Army engineer detachment deployed to the north coast of PNG for 42 days starting in July 1993.Interventions:The soldiers took doxycycline (100 mg) and primaquine (7.5 mg) daily, starting at least two days before they entered the endemic area and continuing for three days after their return to Australia. No primaquine eradication course was given at that time.Main outcome measures: The number of soldiers who developed malaria, plasma drug concentrations and drug side effects.Results:None of the 53 men developed malaria while in PNG. Three developed falciparum malaria two to three weeks after leaving the endemic area, although one of them had taken doxycycline alone because of glucose‐6‐phosphate dehydrogenase deficiency. Nine men developed vivax malaria between three and 40 weeks after leaving PNG, and three had relapses. Doxycycline was generally well tolerated, with only three of the men requiring a change of medication to mefloquine because of adverse gastrointestinal symptoms.Conclusions:Although doxycycline generally provides good protection against malaria infection, it cannot be relied on for causal prophylaxis, even when combined with low dose primaquine. Because the malaria infections occurred only after return to Australia, doxycycline appears to be effective in suppressing malaria while the drug is being taken. Intense, repeated exposure to malaria may require an extended period of chemoprophylaxis on return from an endemic area.