Combination therapy with penicillin and clindamycin has been a mainstay for treatment of invasive group A Streptococcus (iGAS) infections, yet increasing erythromycin resistance may limit such treatment for iGAS strains displaying inducible MLSB phenotypes. The CDC recently reported erythromycin and clindamycin resistance rates for iGAS exceeding 20% in 2017. Here, we investigated 76 iGAS isolates identified at J.W. Ruby Memorial Hospital in West Virginia during 6 quarters of 2020-2021. emm typing was performed using CDC protocol and database. Resistance genes were detected by PCR and sequencing, whereas antimicrobial susceptibility testing was performed in clinical and research laboratories using standard techniques. Median patient age was 42 years (23-86 range). 76.3% (n=58) of isolates were resistant to both erythromycin and clindamycin, which included both inducible (n=48) and constitutive (n=10) resistance. All emm92 (n=44) and emm11 (n=8) isolates were erythromycin resistant, while the remaining 26% (n=17) of resistant isolates comprised 12 emm types. Susceptible isolates included emm89 (n=6) and emm1 (n=2) iGAS. Macrolide resistance was conferred by the plasmid-borne ermT gene in all emm92 isolates and by chromosomally-encoded ermA (n=7), ermB (n=7), and mefA (n=1) in other emm types. Sequence analysis of the erm/mef regulatory regions identified leader peptides and structural hairpin elements, as well as polymorphisms associated with inducible and constitutive resistance. Macrolide-resistant iGAS were typically resistant to tetracycline and aminoglycoside antibiotics. Here, we characterized iGAS infections affecting non-pediatric residents across West Virginia. We showed a shift in emm-type distribution compared to historical and national reports, and dominance of macrolide-resistant isolates, raising concern for emerging resistance to commonly-prescribed antibiotics for iGAS infection.