Leptospirosis is one of the so-called neglected diseases of the Global South, particularly in Latin America and the Caribbean. Its actual incidence and case fatality rate are uncertain, though the latter is likely to be high. To estimate the actual health impact of the disease in the French West Indies, an incidence study was conducted in 2011, utilizing all currently available diagnostic tools: the microagglutination test (MAT), ELISA IgM serology, and PCR. This study included not only hospitalized patients but also, thanks to networks of sentinel general practitioners, outpatients treated by their primary care physicians. The incidence of leptospirosis was estimated at 69 and 61 cases per 100,000 inhabitants per year in mainland Guadeloupe and Martinique, respectively—an incidence more than 100 times higher than that in mainland France during the study period. The results also show that access to PCR diagnosis leads to a number of cases in the French West Indies that is significantly higher than previously reported; it also allows for early diagnosis of the disease, limiting the risk of leptospirosis complications through the prescription of antibiotic treatment. The epidemiology of the disease was also described in terms of severity, demographic characteristics, and seasonality. The results confirm the relevance of establishing an epidemiological surveillance system designed for early warning, closely integrated with a strategy for the prevention and control of the disease.