Objective To investigate antimicrobial resistance in viridans group streptococci (VGS) among patients with and without the diagnosis of cancer in the USA, Canada and Latin America. Methods All bloodstream isolates of VGS collected from SENTRY centers in the Western Hemisphere between January 1997 and December 1999 were tested by reference broth microdilution methods (NCCLS). Results for isolates from patients with cancer were compared to those from other patient populations. Results Overall, 438 unique patient bloodstream isolates of VGS were collected during the study. Percentage susceptible/MIC90 (mg/L) values for antimicrobials tested were as follows: penicillin, 66/1; erythromycin, 60/4; clindamycin, 92/0.12; cefepime, 86/1; trimethoprim-sulfamethoxazole, 80/2; ciprofloxacin, 44/>2: gatifloxacin, 98/0.5; and vancomycin, 100/1. Of these isolates, 70 (16%) were confirmed to be from cancer patients. VGS isolates from cancer patients were less susceptible to more antimicrobials tested than were isolates from non-cancer patients. The greatest differences in susceptibility rates for cancer- versus noncancer-associated VGS isolates were seen for ciprofloxacin (34% versus 46%, P = 0.07) and trimethoprimsulfamethoxazole (64% versus 83%, P < 0.001), two agents which are often used for prophylaxis or as presumptive therapy in cancer patients. Conclusions Susceptibility rates for VGS isolates from cancer patients are lower than those for isolates from patients without a cancer diagnosis. These differences are greatest for agents that have seen widespread prophylactic and empirical use. Ongoing surveillance of VGS infections in this patient population is important and should help to guide therapy decisions.