Regional differences in the prevalence of Panton-Valentine leukocidin (PVL) and PVL isoform-harboring strains as well as in the local population structure of Staphylococcus aureus may influence the clinical spectrum of S. aureus infections.Using a prospective collection of S. aureus isolates from northern Australia, we determined differences between infections caused by (1) PVL(+) and PVL(-) isolates, (2) PVL histidine (H) isoform- and PVL arginine (R) isoform-harboring isolates, and (3) different lineages, including the genetically divergent clonal complex (CC) 75 and the PVL(+) CC93.PVL(+) isolates comprised 54% (128/239) of community-associated methicillin-resistant isolates and 40% (95/239) of methicillin-susceptible S. aureus (MSSA) isolates. There were 113 H isoform- and 110 R isoform-harboring isolates. PVL was associated with truly community-acquired disease, younger age, and presentation with sepsis. We found no differences in infections due to H isoform-harboring isolates, compared with R isoform-harboring isolates. CC93 was the most prevalent lineage. The genetically divergent CC75 caused clinical disease similar to that of other S. aureus clones.PVL(+) and PVL(-) infections are clearly distinct. MSSA contributes a large but underrecognized burden of PVL(+) disease. Compared with elsewhere in the world, there is a relative abundance of the clade that contains CC93 and CC121 in both northern Australia and Asia.