Objective To explore the significance of monitoring the blood peak concentration of sulfamethoxazole (SMZ) to learn the efficacy and safety of compound SMZ (SMZco) tablets in the treatment of Pneumocystis jirovecii pneumonia (PJP) in patients with non-human immunodeficiency virus (HIV). Methods Clinical data of PJP infected patients with non-HIV hospitalized in Ruijin Hospital, from January 2019 to May 2023 were enrollled, and the relationship between the peak plasma concentration of SMZ and the efficacy and occurrence of adverse reactions was retrospectively analyzed. Results A total of 47 patients were included in this study. The peak plasma concentration of SMZ ranged from 87.49 mg/L to 334.31 mg/L, the median (interquartile distance) was 168.62 (79.72) mg/L, and the peak plasma concentration in 64% of patients was >150 mg/L. The 30-day all-cause mortality of the patients was 28%，and the positive response rate was 66%. Among them, there was no statistical difference in 30-day all-cause death and treatment positive response rate between the patients with peak concentration ≤150 mg/L and the patients with peak concentration of SMZ >150 mg/L. In terms of safety, a total of 29 (62%) patients showed adverse reactions. The incidence of thrombocytopenia (40% vs 6%, P=0.025), decreased hemoglobin (37% vs 0, P=0.013) and serious adverse reactions (43% vs 12%, P=0.026) were higher in the patients with SMZ peak concentration >150 mg/L than those in the patients with SMZ peak concentration <150 mg/L. The incidence of serious adverse reactions was higher in the patients with a peak concentration of SMZco >150 mg/L. Conclusions The results of the study showed that as SMZco tablets were used in the treatment of non-HIV patients infected with PJP, those with a peak plasma concentration ≤150 mg/L of SMZ could achieve comparable efficacy, and their risk of serious adverse reactions was less than that of the patients with a peak plasma concentration >150 mg/L. It is suggested that the plasma peak concentration of SMZ should be monitored regularly.