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Background and Purpose: Radiation pneumonitis is a common complication of thoracic radiation.Our clinical experience suggested that Pneumocystisjiroveci pneumonia (PCP) contributes significantly to the mortality rate of chemoradiotherapy-induced severe radiation pneumonitis (SRP) in lung cancer patients.We evaluated the efficacy of PCP prophylaxis during the treatment of SRP.Materials and Methods: We retrospectively analyzed 24 lung cancer patients treated with chemoradiotherapy who developed SRP between 2009 and 2011.SRP was defmed as grade ≥3 radiation pneumonitis using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.Patients who had received the typical corticosteroid treatment constituted the standard group, and those who had additionally received trimethoprim-sulfamethoxazole comprised the prophylaxis group.PCP incidence and the mortality rates of the 2 groups were compared.Results: The incidence of PCP infection was 43% in the standard group and 0% in the prophylaxis group (p =0.024).After a 3-month post-diagnosis follow-up, 5 of the 24 patients, all from the standard group, died; PCP infection was the cause of death in 3 patients.Conclusions: Trimethoprim-sulfamethoxazole prophylaxis can substantially reduce the incidence of PCP and the mortality rate from SRP in lung cancer patients who develop SRP after treatment with chemoradiotherapy.