We prospectively studied 260 episodes of bacteremia that occurred over a 6-year period in neutropenic patients with cancer. Twenty-three episodes were caused by viridans streptococci. Thirteen (57%) of these strains were penicillin-resistant (MICs of penicillin ranged from 0.25 micrograms/mL to 8 micrograms/mL). Ten of the 13 penicillin-resistant strains (77%) were highly resistant to penicillin (MIC, > or = 4 micrograms/mL). Rates of bacteremia due to highly penicillin-resistant viridans streptococci increased significantly from zero episodes per 1,000 admissions in 1987 to 17 episodes per 1,000 admissions in 1992 (P = .003). In a comparison between penicillin-resistant and penicillin-susceptible viridans streptococci bacteremia, the administration of beta-lactam antibiotics during the previous 2 weeks was the only factor significantly associated with penicillin-resistant cases: 9 (69%) of 13 patients with penicillin-resistant bacteremia had received beta-lactams vs. 2 (20%) of 10 patients with penicillin-susceptible bacteremia (P = .036). These findings may have significant clinical implications in the choice of both antimicrobial prophylaxis and empirical antibiotic regimens.