The clinical utility of naproxen as an antipyretic agent was examined in the differential diagnosis of fever of undetermined origin in patients with cancer. Twenty-two patients with cancer and fever of undetermined origin for more than seven days were treated with naproxen to control fever when there was no evidence of infection after a careful initial evaluation, and in most cases, after failure of antibiotic therapy. In final analysis, none of five patients with infectious fever had responses to naproxen. In contrast, 14 of 15 patients with neoplastic fever showed a prompt, complete, and sustained lysis of fever within 24 hours after the initiation of naproxen treatment, and the patients also showed symptomatic improvement. One patient with neoplastic fever who did not have a response to naproxen had lysis of fever after the removal of necrotic tumor tissue. Two patients with fever from connective tissue disease had a partial lysis of fever in response to naproxen. These data suggest that naproxen specifically produces the lysis of neoplastic fever and, therefore, is a useful agent in assisting in the differential diagnosis of infectious fever and neoplastic fever in patients with cancer and fever of undetermined origin.