Several authors have reported interstitial pneumonia (IP) during rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy, while others have encountered Pneumocystis jirovecii pneumonia during rituximab-combined bi-weekly CHOP. Herein, we report that 13 of 90 (14%) patients developed IP during R-CHOP therapy, compared with none of 105 patients treated with CHOP alone as a historical control. There were no differences in baseline data between patients undergoing the two therapies. Among R-CHOP-treated patients, serum beta-D-glucan was increased in 8 of 12 (75%) IP patients compared with none of 30 non-IP patients examined. In five IP patients who underwent sputum evaluation, two were positive for P. jirovecii by the polymerase chain reaction and another two were positive for Candida albicans. No other organisms were detected as causative pathogens. Treatment with steroids, sulfamethoxazole-trimethoprim (ST), and antifungals was effective. Our results suggest that R-CHOP raises the incidence of IP, possibly through increasing the susceptibility to P. jirovecii and fungal infection. The need for prophylactic antifungals and ST during R-CHOP should be evaluated by randomized controlled trials.