Group A beta-haemolytic streptococcus (GAS) causes a variety of infections, including life-threatening illnesses. Although the species is uniformly penicillin susceptible, resistance to other antibiotics is becoming more common. We studied the prevalence of resistance and associated factors in a nationwide, prospective, population-based study of invasive infections in Israel. Isolates were collected in collaboration with 24 hospitals in Israel during 1996-1999. Minimal inhibitory concentrations (MICs) of erythromycin (ERY), clindamycin (CLI) and tetracycline (TET) were determined as well as ERY and TET resistance phenotypes and genotypes. Five hundred isolates were examined: 136 (27.2%) were not susceptible to TET, 10 (2.0%) to ERY and 5 (1%) to CLI. ERY resistance was associated with emm types 12 and 83 (P<0.001 for both). MICs of TET had a bimodal distribution distinguishing sensitive and resistant populations. Non-susceptibility to TET was mainly due to the presence of tet(M) and was associated with T types 3, 3/13/B3624 and 9 and emm types 9, 33, 64, 73, 74, 76, 77 and 83. TET susceptibility was associated with T types 1, 2 and 11, emm types 1-4, 11, 12, 22, 26 and 75 and the presence of speA and speC. In Israel, resistance of invasive GAS isolates to ERY remains low and is associated with specific T and emm types, as is TET resistance. TET resistance is less frequent than previously reported in Israel and is associated with a lower prevalence of speA and speC.