Q fever is an emergent disease in French Guiana. We compared the incidence clinical and serologic profiles between patients from Cayenne, French Guiana and Marseille in metropolitan France during a four-year period. The annual incidence of diagnosed acute Q fever was significantly higher in Cayenne (17.5/100,000) than in Marseille (1.9/100,000) (P = 0.0004), but not the annual incidence of endocarditis (1.29 versus 0.34/100,000). Most patients had fever (97%) and pneumonia (83%) in Cayenne versus 81% and 8% in Marseille (P < 0.0001 and P < 0.0001, respectively) but transaminitis was more common in patients from Marseille (54% versus 32%; P < 0.0001). The proportion of patients with cardiovascular infections was significantly lower in Cayenne (7%) than in Marseille (17%) (P = 0.017), although they showed a stronger immune response with higher levels of phase I IgG (P = 0.024). The differing epidemiology, clinical, and serologic responses of patients from Cayenne and Marseille suggest a different source of infection and a different strain of Coxiella burnetii.