While described in the past, the frequency and degree of fatigue associated with symptomatic coccidioidomycosis has never been quantified. Using the Fatigue Severity Scale (FSS), severe fatigue (FSS score = 41) was found in 65% of cases of active coccidioidomycosis compared to 42% in cohort of control subjects with chronic medical diseases (P=0.024). Fatigue in patients with symptomatic coccidioidomycosis declined significantly over four months (P=0.023). Severe fatigue in patients with symptomatic coccidioidomycosis was significantly associated with low body mass index (BMI; P=0.024) but was not significantly associated with either serum leptin (r2=0.078, P=0.261) or serum TNF-alpha (r2=0.028, P=0.504) concentrations. Severe fatigue is a common condition among patients with active coccidioidomycosis and is associated with a declining BMI.