Background: In French Guiana, a recent study has shown that a major part of the histoplasmosis incidence temporal fluctuations could be explained by climatic factors and thus postulated that disseminated histoplasmosis cases could be in a large proportion due to new infections. The description of the seasonal pattern of histoplasmosis could potentially help to test this new hypothesis. Patients and methods: A study using prospective data from the French Hospital Database for HIV was conducted in order to determine seasonal variations of the incidence of first cases of disseminated histoplasmosis in HIV persons in Cayenne, French Guiana. Single failure Cox proportional hazards models were used. Results: After adjusting for CD4 counts and antiretroviral treatment, the incidence of disseminated histoplasmosis was significantly higher during the Short Wet Season-Long Dry Season than during the Short Dry Season-Long Wet Season (Adjusted Hazard ratio 1.7 (1.1-2.5), P= 0.01). Conclusion: This result gives both valuable epidemiologic information to clinicians and a supplementary argument in favour of the hypothesis that an important proportion of cases were due to recent exposure. Therefore, the use of a primary prophylaxis must be discussed in French Guiana.