Background: The possible myelosuppression side effect of Trimethoprim-Sulfamethoxazole (TMP-SMX) on primary immune deficiency (PID) patients has not been established yet.Objective: Identify if the PID patients are at higher risk of developing myelosuppression secondary to the use of TMPSMX.Methods: Retrospective, three groups study, of PID patients (on and off TMP-SMX prophylaxis) and urinary tract infection (UTI) patients received prophylaxis TMP-SMX. Data about CBC results (WBC, ANC, Lymphocytes, RBC, Hemoglobin, and Platelet counts) at baseline, first, and maximum myelosuppression observed during the period of TMP-SMX administration were collected.Results: A total of 122 patients were included in this study (41 PID patients on TMP-SMX prophylaxis, 45 PID patients not on TMP-SMX prophylaxis, and 36 UTI patients on prophylaxis TMP-SMX). There are significant differences noticed in the percentage of patients who developed clinical myelosuppression (i.e. less than normal value for age) in ANC (39.0% vs. 8.9% vs. 16.7%, p = 0.002), RBC (36.6% vs. 13.3% vs. 13.9%, p = 0.014), WBC (41.5% vs. 13.3% vs. 13.9%, p = 0.003), and platelet (24.4% vs. 15.6% vs. 2.8%, p = 0.028) in group 1, 2, and 3, respectively. Significant difference in myelosuppression between the groups was most likely due to the combination of TMP-SMX effect on PID patients rather than the disease or the drug itself.Conclusions: Primary immune deficiency (PID) patients are at higher risk of developing myelosuppression secondary to TMP-SMX prophylaxis (especially ANC) comparing to immune-competent patients or other PID patients who did not receive prophylactic TMP-SMX. Future larger prospective study is required to confirm this association.