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Primary prophylaxis for Pneumocystis jirovecii pneumonia in patients receiving rituximab. BACKGROUND: Although previous studies suggested that rituximab increases the risk of Pneumocystis jirovecii pneumonia (PJP), it is uncertain whether its primary prophylaxis for PJP is justified. RESEARCH QUESTION: Does the benefit of primary prophylaxis for PJP in patients receiving rituximab treatment outweigh the potential risk of the prophylaxis? STUDY DESIGN AND METHODS: This retrospective study included 3524 patients (hematologic diseases=2500; rheumatic diseases=559; pre/post-solid organ transplantation=465) first exposed to rituximab between 2002 and 2018 in a tertiary referral center in South Korea. Patients were classified into a control group (n=2523) and a prophylaxis group (n=1001) according to the administration of prophylactic TMP-SMX during the first 28 days after the start of rituximab (intention-to-treat analysis). In addition, exposure to TMP-SMX was examined as a time-varying variable (time-varying analysis). Primary outcome was the prophylactic effect of TMP-SMX on the 1-year incidence of PJP. Inverse probability of treatment weights was applied to minimize the baseline imbalance. Secondary outcome included the incidence of adverse drug reactions (ADRs) related to TMP-SMX. RESULTS: Over 2759.9 person-years, 92 PJP infections occurred, with a mortality rate of 27.2%. The prophylaxis group showed a significantly lower incidence of PJP (adjusted sub-distribution hazard ratio (aSHR), 0.20 [95% CI, 0.10-0.42]) than the control group. This result was consistent with the results of time-varying analysis, in which only one PJP infection occurred during TMP-SMX administration (aSHR, 0.01 [0.003-0.16]). The incidence of adverse drug reactions (ADRs) related to TMP-SMX was 18.1 (14.6-22.2)/100 person-years, and most were of mild-to-moderate severity. Based on ten severe ADRs, the number needed to harm was 101 (61.9-261.1), whereas the number needed to prevent one PJP infection was 32 (24.8-39.4). INTERPRETATION: TMP-SMX prophylaxis significantly reduces PJP incidence with a tolerable safety profile in patients receiving rituximab treatment.