BACKGROUND Since the appropriate antibiotic duration for uncomplicated Staphylococcus aureus (S. aureus) bacteremia (u-SAB) in an immunocompromised state is still unclear, physicians are likely to extend antibiotic therapy from 2 weeks to 4-6 weeks. To examine the appropriate duration of antibiotic therapy for u-SAB, we performed this study. METHODS We reviewed all patients with u-SAB at our institute seen between January 2020 and August 2023. A total of 51 patients were enrolled, and they were divided into the following two groups by antibiotic duration: longer duration group ≥28 days after blood culture negativity, and shorter duration group. Then, the patients were matched by a propensity score using the covariates of age, sex, qSOFA, and CCI. The primary outcome was to identify the prognosis by duration of antibiotic treatment. RESULTS After propensity score matching, all-cause 30-day mortality was 0 % in both groups. Hence, there was no significant difference in all-cause 90 days mortality (19.0% vs 9.5%, p = 0.33) or recurrence (9.5%% vs 0%, p = 0.22). Before propensity-score matching, we found that a serum level of CRP 2.0 mg/dL and greater after intravenous antibiotic treatment was one of the poor prognostic factors. The cut-off value of serum CRP level was 2.0 mg/dL with a sensitivity of 82.1% and a specificity of 75.0%. CONCLUSIONS We suggested that 4-6 weeks of antibiotic treatment for immunodeficient u-SAB patients was unnecessary. Moreover, the serum level of CRP after completion of IV antibiotic treatment could be a prognostic marker for u-SAB.