Background <p><i>Pneumocystis jirovecii</i> pneumonia (PCP) is a severe opportunistic infection. Trimethoprim-sulfamethoxazole (SXT) is the first-choice treatment for PCP in human immunodeficiency virus (HIV)-infected and non-HIV-infected patients. However, the high incidence of adverse events makes treatment with SXT difficult. The risk factors for these adverse events in patients with non-HIV PCP remain unclear.</p> Methods <p>In this multicenter, retrospective, observational cohort study, we investigated these risk factors by analyzing data from patients with non-HIV PCP treated with SXT between June 2006 and March 2021 across three institutions. Patients were divided into two groups based on the presence of grade 3 or higher adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0: the adverse event (<i>n</i> = 74) and no adverse event (<i>n</i> = 62) groups. Patient characteristics were compared, and multivariate regression analysis was used to identify factors contributing to adverse events. We also investigated the relationship between treatment failure and adverse events.</p> Results <p>Baseline characteristics showed notable variations between the groups, notably in serum sodium, serum potassium levels, and the initial trimethoprim dose per weight. Logistic regression analysis revealed significant associations among adverse events and these three baseline variables. In the treatment failure group, the most frequent adverse events included skin rashes, hyponatremia, and hyperkalemia.</p> Conclusions <p>Pretreatment serum sodium and potassium levels and the initial SXT dose per weight were identified as independent risk factors for developing CTCAE grade 3 or higher adverse events associated with SXT treatment for non-HIV PCP. Further large-scale, prospective studies are essential to confirm these results.</p>