We compared the proportion of cases of community-associated and healthcare-associated methicillin-resistant Staphylococcus aureus (CA-MRSA and HA-MRSA, respectively) bacteraemia among patients at five hospitals in the Gauteng and Western Cape provinces in South Africa and described the molecular characteristics and antimicrobial susceptibility trends. This was a cross-sectional study using data collected by enhanced surveillance for S. aureus bacteraemia. A total of 2511 cases of S. aureus bacteraemia were identified from January 2013 to January 2016. Among 1914 cases of S. aureus, 557 (29.1%) cases were identified as MRSA infection. Forty-four cases (44/1914 [2.3%] of all S. aureus cases) were considered CA-MRSA infection and 513/1914 (26.8% of all cases) had HA-MRSA infection; the majority were neonates. CA-MRSA constituted 7.9% (44/557) of all cases of MRSA infection. Staphylococcus aureus isolates demonstrated significantly reduced susceptibility to the following classes of antimicrobial agents: macrolides, tetracyclines, aminoglycosides and cotrimoxazole, in 2015 compared to 2013 (p < 0.05). Of the 557 MRSA isolates, 484 (87%) were typed for SCCmec elements and spa types: the most common SCCmec type was type III (n = 236, 48.76%), followed by type IV (n = 144, 29.76%). The most common spa types were t037 (n = 229, 47.31%) and t1257 (n = 90, 18.60%). Of 28 isolates selected for multilocus sequence typing (MLST), the most common sequence types (STs) were ST239 and ST612 of clonal complex 8 (CC8) (n = 8 each) and a novel ST (ST4121) was obtained for one isolate. This study demonstrates that S. aureus bacteraemia is common in South African academic centres and characterised by HA-MRSA SCCmec types III and IV. A small proportion of CA-MRSA cases were caused by a few different sequence types.