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Aims: The objective of this study was to determine the effectiveness and safety of cefazolin vs. antistaphylococcal penicillin (ASP) in the treatment of methicillin-sensitive Staphylococcus aureus (MSSA) bacteraemia., Methods: The databases of PubMed, Embase and Cochrane Central were used to identify comparative trials of cefazolin vs. ASP in MSSA bacteraemia. Meta-analysis of included trials was performed to assess any differences regarding mortality, clinical cure, recurrence and withdrawal from adverse effects between groups. Data were analysed using fixed effect model. Studies were weighted using Mantel-Haenszel methodology. Heterogeneity was calculated using the I 2 statistic., Results: Nine retrospective and one prospective trials were identified involving 4728 patients, 2954 with ASP and 1774 with cefazolin. Meta-analysis showed a lower mortality rate with cefazolin vs. ASP using fixed effect model [risk ratio (RR) 0.78, 95% confidence interval (CI) 0.69-0.88, P < 0.0001] with borderline high heterogeneity (I 2  = 51%). Clinical cure was noted more often with cefazolin (RR 1.09, 95% CI 1.02-1.17, P = 0.02), although no difference was noted with relapse (RR 1.29, 95% CI 0.96-1.74 P = 0.09). Analysis also showed more withdrawals from adverse events with ASP vs. cefazolin (RR 0.27, 95% CI 0.16-0.47, P < 0.00001). A minority of patients enrolled in these trials were admitted to the intensive care unit or had endocarditis (11.4% with ASP and 9% with cefazolin)., Conclusion: Our meta-analysis of retrospective data demonstrate that cefazolin is more effective and safer ASP in patients with MSSA bacteraemia from various causes. Low quality of trials, borderline high heterogeneity, and possible publication bias may limit the validity of our findings. Randomized trials are needed to confirm these findings., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)