An in vitro model was used to compare the effects of linezolid, clindamycin, and penicillin, alone and in combination, on streptococcal pyrogenic exotoxin A (SPE A) release against virulent group A streptococci (GAS). All regimens exhibited lower (P < 0.05) SPE A release at 1 h than those with penicillin alone. Linezolid and clindamycin, alone or in combination with penicillin, may optimize the treatment of GAS infections by reducing bacterial burden and exotoxin release.