Decreased adiponectin (APN) levels have been detected in patients with osteonecrosis of the femoral head (ONFH). The scope of this study was aimed to explore the relationship between serum APN levels and disease severity in nontraumatic ONFH patients. Ninety two nontraumatic ONFH patients and 92 healthy controls were enrolled for this study following the estimation of sample size. Serum APN concentrations were examined by enzyme-linked immunosorbent assay (ELISA). The radiographic progression was determined by Ficat grading system. The clinical severity was evaluated by visual analog scale (VAS), Harris hip scores (HSSs) and Western Ontario and McMaster University Osteoarthritis Index (WOMAC) scores. Serum APN levels were significantly lower in ONFH patients than in healthy controls. Serum APN levels were significantly lower in patients with Ficat stage 4 ONFH than in patients with stage 3 ONFH, and APN levels in patients with stage 3 were lower compared with stage 2. Serum APN levels were negatively correlated with the Ficat grading system. In addition, serum APN levels were also negatively related to VAS and WOMAC scores and positively associated with HSSs. Decreased serum APN levels may reflect disease severity of nontraumatic ONFH.