The association between chemoprophylaxis and delayed onset of falciparum malaria was investigated in a retrospective study of 477 nonimmune cases reported to the UK Malaria Reference Laboratory (MRL) who had used either mefloquine (n = 56), chloroquine-proguanil (n = 90) or no chemoprophylaxis (n = 331). For holiday and short-term travellers using mefloquine the time between arrival in the UK and diagnosis was found to be significantly longer than for chloroquine and proguanil (C-P) users or for those who had not used prophylaxis at all (P < 0.004). This delay was primarily due to a later onset of symptoms. C-P use was not associated with delay in onset of symptoms or diagnosis when compared to not using prophylaxis. Possible reasons for the findings are discussed. Mefloquine may continue to exert a partially suppressive effect on resistant strains of Plasmodium falciparum (Pf). That chloroquine with proguanil was not found to have such an effect may be due to poor compliance to proguanil or differences in the mode of action and range of parasite resistance to the two regimens. Differences in drug compliance may be one reason why only mefloquine users on holiday or short-term journeys experienced delays to onset of disease. Drug compliance amongst cases of breakthrough malaria on chemoprophylaxis may be lower than is generally recognized. It is important for clinicians and travellers to be aware that the onset of falciparum malaria may be delayed by mefloquine prophylaxis.