Background Current guidelines recommend continuation of atovaquone-proguanil (AP) malaria prophylaxis for 7 days after leaving Plasmodium falciparum endemic areas. Evidence from clinical studies suggests that discontinuation of AP 1 day after exposure ends may be safe and effective. Our objective was to assess the effectiveness of short-course AP prophylaxis among travelers to sub-Saharan Africa. Methods To detect prophylactic failures associated with short-course AP prophylaxis discontinued 1 day after return, we conducted active surveillance during the years 2010 and 2011, by a retrospective telephone survey 1 to 6 months after travelers' return. Passive surveillance data were obtained from the Israel Ministry of Health (MOH) malaria registry. Results Among 485 travelers to sub-Saharan Africa (cumulative exposure of 4,979 days), 421 (87%) discontinued AP 1 day after leaving the endemic region (cumulative exposure of 4,337 days). None of the 485 travelers reported malaria infection. The MOH malaria registry survey included 363 P. falciparum-infected patients during the years 2003 to 2011. The majority (n = 305; 84%) did not use any malaria prophylaxis. None of the patients had used AP (neither regular nor short course AP) for malaria prophylaxis. Conclusions We did not detect prophylaxis failures among a group of travelers who discontinued AP prophylaxis 1 day after leaving malaria-endemic areas. Passive surveillance in Israel did not detect any P. falciparum cases among AP users. We recommend further validation of our findings by clinical trials, prospective studies, and active surveillance in larger cohorts to assess the effectiveness of short-course AP prophylaxis in travelers.