Impetigo is a skin infection caused by Group A Streptococcus (GAS) that is highly prevalent in Indigenous Australian Aboriginal and Torres Strait Islander communities. Approximately 45% of Indigenous children living in northern Australia are affected by impetigo at any given time, which is the highest prevalence in the world. While GAS is considered a key driver of clinical impetigo, co-infection with S. aureus is common, and both pathogens can cause a number of severe complications that include sepsis, and in the case of GAS, post-infectious immune sequelae. In an effort to reduce the burden of impetigo in endemic populations, the antibiotic combination cotrimoxazole (SXT) has shown considerable promise. However, with expanding use there is concern that resistance could emerge. Resistance to SXT requires resistance to each of the component antibiotics, sulfamethoxazole (SX) and trimethoprim (TP). While the requirement for resistance to both TP and SX reduces the likelihood of SXT resistance occurring, there is concern that genes or mutations that confer resistance to TP and/or SX might disseminate within Gram-positive skin pathogens while remaining undetected by routine clinical microbiology surveillance. In particular, the TP-resistance gene dfrG is already circulating in ~10% of methicillin-resistant S. aureus (MRSA) isolates in northern Australia. In this study, through a combination of phenotypic testing, in vitro selection and genomic analysis, we show that dfrG does not confer SXT resistance in GAS, even for strains that have also acquired high-level SX resistance. This important finding alleviates the concern that dfrG has the potential to lead to SXT-resistant GAS (and potentially MRSA) infections in Northern Australia, and suggests that the potential for GAS to become resistant to SXT as a result of horizontal gene transfer from MRSA coinfections is extremely low.