IMPORTANCE Q fever remains widespread throughout the world; the disease is serious and causes outbreaks and deaths when complications are not detected. The diagnosis of Q fever requires the demonstration of the presence of Coxiella burnetii and the identification of an organic lesion. OBJECTIVE To describe the hitherto neglected clinical characteristics of Q fever and identifying risk factors for complications and death. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study conducted from January 1, 1991, through December 31, 2016, included patients treated at the French National Reference Center for Q fever with serologic findings positive for C burnetii and clinical data consistent with C burnetii infection. Clinical data were prospectively collected by telephone. Patients with unavailable clinical data or an unidentified infectious focus were excluded. MAIN OUTCOMES AND MEASURES Q fever complications and mortality. RESULTS Of the 180 483 patients undergoing testing, 2918 had positive findings for C burnetii and 2434 (68.8% men) presented with clinical data consistent with a C burnetii infection. Mean (SD) age was 51.8 (17.4) years, and the ratio of men to women was 2.2. At the time of inclusion, 1806 patients presented with acute Q fever, including 138 with acute Q fever that progressed to persistent C burnetii infection, and 766 had persistent focalized C burnetii infection. Rare and hitherto neglected foci of infections included lymphadenitis (97 [4.0%]), acute Q fever endocarditis (50 [2.1%]), hemophagocytic syndrome (9 [0.4%]). and alithiasic cholecystitis (11 [0.4%]). Vascular infection (hazard ratio [HR], 3.1: 95% CI, 1.7-5.7; P < .001) and endocarditis (HR. 2.4; 95% CI, 1.1-5.1; P = .02) were associated with an increased risk of death. Independent indicators of lymphoma were lymphadenitis (HR, 77.4; 95% CI, 21.2-281.8; P < .001) and hemophagocytic syndrome (HR, 19.1; 95% CI, 3.4-108.6; P < .001). The presence of anticardiolipin antibodies during acute Q fever has been associated with several complications, including hepatitis, cholecystitis, endocarditis, thrombosis, hemophagocytic syndrome, meningitis, and progression to persistent endocarditis. CONCLUSIONS AND RELEVANCE Previously neglected foci of C burnetii infection include the lymphatic system (ie, bone marrow, lymphadenitis) with a risk of lymphoma. Cardiovascular infections were the main fatal complications, highlighting the importance of routine screening for valvular heart disease and vascular anomalies during acute Q fever. Routine screening for anticardiolopin antibodies during acute Q fever can help prevent complications. Positron emission tomographic scanning could be proposed for all patients with suspected persistent focused infection to rapidly diagnose vascular and lymphatic infections associated with death and lymphoma, respectively.