This investigation was conducted in response to a report of an increased number of malaria cases among United States Embassy personnel in Kampala, Uganda in the spring of 1992. The objectives of the investigation were to determine if an outbreak had occurred, to identify potential risk factors for malaria in this population, and to assess the effectiveness of various chemoprophylactic regimens. The risk of developing malaria during the first half of 1992 was more than six times greater than during the same time period in 1991 (relative risk [RR] = 6.6, 95% confidence interval [CI] = 1.6–27.8) and almost seven times greater than all the previous six years combined (RR = 6.8, 95% CI = 2.9–15.9). In this outbreak, children and young adults less than 20 years of age had more than a three-fold increase in risk (RR = 3.7, 95% CI = 0.7–19.8) than those in the 20–39-year-old age group. African-Americans had a six-fold increased risk compared with Caucasians (RR = 6.0, 95% CI = 1.6–22.7). Those who did not take any drug prophylaxis were 10 times more likely to develop malaria (RR = 10.0, 95% CI = 2.7–37.0) than those who took mefloquine, doxycycline, or chloroquine plus proguanil. In this setting, weekly mefloquine was 82% more effective, and chloroquine plus proguanil was 92% more effective than weekly chloroquine alone. This outbreak underscores the need for compliance with appropriate chemoprophylactic regimens in preventing malaria infection.