Staphylococcus aureus is the most common bacterial pathogen in hospitalized patients, and is a leading cause of bacteremia. Current guidelines recommend when the etiology of infection is known or suspected, the antimicrobial most cost-effective, least toxic, and most narrow in spectrum be used. To evaluate treatment of PSSA bacteremia with penicillin versus other antibiotics, a retrospective cohort study was conducted at a tertiary care center in Western Massachusetts using data collected from 2003 to 2013. One-hundred and eight patients with PSSA bacteremia were included. The primary exposure was defined as treatment with penicillin within 3 days of the first positive culture. The primary outcome was duration of bacteremia, with length of hospital stay and 30-day readmission as secondary outcomes. Data were abstracted from administrative databases and medical records, and multivariable and propensity-score-adjusted analyses were conducted. Overall, there was no difference in duration of bacteremia according to treatment (p=0.77), and a non-significant 25% increase in length of stay post-culture was observed in patients not receiving penicillin (p=0.34). Propensity-score-adjusted analyses also did not yield significant differences in clinical outcomes. The results of this study suggest no significant associations between treatment with penicillin versus other antibiotics and clinical outcomes. Given the low cost and decreased risk of developing multidrug-resistant bacteria, PSSA bacteremia should be treated preferentially with penicillin. However, given the small sample size, and the potentially wide range of antibiotics used in place of penicillin, caution should be exercised in interpreting these results. Larger multi-site studies are needed to address these associations.