From March 1998 to June 1999, we studied 63 sequential blood culture isolates of viridans group streptococci which showed a 49% resistance to erythromycin. A high level of resistance to penicillin (46%) was also found. A statistically significant correlation was detected between the two types of resistance. The erythromycin-resistant strains were phenotypically and genotypically characterized, and no differences were found between the resistance to penicillin and the M or MLS(B) phenotypes. The penicillin-erythromycin-resistant strains included: 16 S. mitis, five S. sanguis and one S. salivarius. The rank order of activity (% of susceptibility) for all 14 agents against 31 erythromycin- resistant isolates was the following: vancomycin = rifampicin (100) > chloramphenicol (98) > meropenem (65) > cefotaxime (61) > amoxicillin- clavulanic acid (42) > cefepime = ciprofloxacin (39) > tetracycline = trimethoprim-sulfamethoxazole (36) > cefuroxime (32) > penicillin = ampicillin = cefaclor (29). The species S. milleri and S. bovis were the most susceptible. The most resistant strains were two S. mitis and one S. sanguis and showed multiresistance to six different groups of antimicrobial agents. The frequent association between macrolide resistance and resistance to other antimicrobial agents suggests that the susceptibility of all clinically significant isolates needs to be evaluated and alternative agents for the prevention and treatment of viridans group streptococci infections should be identified.