Abstract An historical prospective study was performed on 5120 Italian soldiers deployed in Somalia and Mozambique in 1992–1994, to determine compliance and tolerability of long-term malaria chemoprophylaxis with chloroquine plus proguanil (C + P) and with mefloquine. Compliance with C + P among 3734 soldiers on duty in Somalia for 3·8 ± 1·8 months and with mefloquine among 1386 soldiers on duty in Mozambique for 3·4 ± 1·5 months was 90·3% and 95·7%, respectively ( P < 0·01). Chemoprophylaxis curtailment rate due to side-effects was 1·5% among C + P users and 0·9% among mefloquine users ( P = NS). Compliance with chemoprophylaxis and medication curtailment rate due to side-effects did not change significantly for either C + P or mefloquine, even after 3 months of continuous prophylaxis. Chemoprophylaxis curtailment rate was significantly lower in subjects aged ⩽25 years than in older subjects (1·3% vs. 2·5% for C + P [ P < 0·05] and 0·4% vs. 3·3% for mefloquine [ P < 0·01]). These results further support the evidence that both C + P and mefloquine regimens may be safely used in long-term malaria chemoprophylaxis. Moreover, weekly mefloquine seems easier to perform than C + P and not to increase prophylaxis discontinuation due to side-effects. Mefloquine regimen should therefore be considered the elective chemoprophylaxis for groups at particular risk of chloroquine-resistant Plasmodium falciparum malaria and especially for young male subjects.