The nature of polymorphonuclear leukocyte (PMN) cell death strongly influences resolution of inflammatory episodes, and may also exacerbate adverse pathologies in response to infection. In this study, we investigated PMN cell death mechanisms following infection by virulent group A Streptococcus (GAS). Human PMNs were infected in vitro with a clinical, virulent GAS isolate and avirulent derivative strain, and compared for phagocytosis, reactive oxygen species (ROS) production, mitochondrial membrane depolarisation and specific apoptotic markers. C57BL/6 mice were intradermally infected with both strains to observe elicited effects on murine PMNs in vivo. Human PMNs phagocytosed virulent GAS less efficiently, produced less ROS, and underwent reduced mitochondrial membrane depolarisation than avirulent GAS strains. Morphological and biochemical analyses revealed human PMNs infected with avirulent GAS exhibited nuclear fragmentation and caspase-3 activation consistent with an anti-inflammatory PMN apoptotic phenotype. Conversely, virulent GAS induced PMN vacuolisation and plasma membrane permeabilisation, leading to oncotic cell death. Cutaneous infection of C57BL/6 mice with virulent GAS engendered localised infiltration of murine PMNs, and cells associated with virulent GAS infection exhibited reduced apoptotic potential, whereas avirulent GAS infection was associated with tissue PMN apoptosis. We propose differences in PMN cell death mechanisms influence inflammatory responses to infection by GAS.