Introduction: There is a pressing need for effective measures to prevent the spread of cholera. Our systematic review assesses the effects of chemoprophylaxis in preventing cholera among exposed contacts. Methods and Findings: We considered published and unpublished reports of studies up to July 2011. For this we searched: PubMed (1966 to July, 2011), Embase (1980 to July 2011), Cochrane Central Register of Controlled Trials (6; 2011), LILACS (1982 to July, 2011), the International Clinical Trials Registry Platform (July 2011) and references of identified publications. We included controlled clinical trials (randomized and non-randomized) in which chemoprophylaxis was used to prevent cholera among patient contacts. The main outcome measures were hospitalization and laboratory diagnosis of cholera in contacts for cholera patients. We assessed the risk of bias. We identified 2638 references and these included 2 randomized trials and 5 controlled trials that added up to a total of 4,154 participants. The risk of bias scored high for most trials. The combined results from two trials found that chemoprophylaxis reduced hospitalization of contacts during the follow-up period by 8-12 days (2826 participants; RR 0.54 95% CI 0.40-0.74;I 2 0%). A meta-analysis of five trials found a significant reduction in disease among contacts with at least one positive sample who received chemoprophylaxis during the overall follow-up (range 4-15 days) (1,414 participants; RR 0.35 95% CI 0.18-0.66;I 2 74%). A significant reduction in the number of positive samples was also found with chemoprophylaxis (3 CCT; 6,918 samples; RR 0.39 95% CI 0.29-0.51;I 2 0%). Conclusion: Our findings suggest that chemoprophylaxis has a protective effect among household contacts of people with cholera but the results are based on studies with a high risk of bias. Hence, there is a need for adequate reliable research that allows balancing benefits and harms by evaluating the effects of chemoprophylaxis.