Between 1972 and 1989, the incidence of viridans streptococcal bacteremia at the University of Texas M. D. Anderson Cancer Center in Houston increased from one case per 10,000 admissions to 47 cases per 10,000 admissions (P less than .0001). A shock syndrome characterized by hypotension, rash, palmar desquamation, adult respiratory distress syndrome, and occasionally death developed in 26% of cases of streptococcal septicemia but in only 4% of cases of septicemia involving other gram-positive bacteria (P = .0005). The risk of streptococcal infection increased with the prophylactic administration of trimethoprim-sulfamethoxazole or a fluoroquinolone (P less than .0001) and with profound neutropenia (P less than .0001). Treatment of chemotherapy-induced gastritis with antacids or with histamine type 2 (H2) antagonists was associated with a sevenfold increase in risk (P less than .001), while sucralfate therapy did not increase risk (P = .65). Streptococcal infection may result from gastric overgrowth of organisms resistant to trimethoprim-sulfamethoxazole in an antacid- or H2 antagonist-induced alkaline environment, with the gastrointestinal tract ulceration caused by antineoplastic therapy providing a convenient portal of entry. In patients receiving chemotherapy, replacement of antacids or H2 antagonists by an acid-sparing regimen should be considered to preserve the natural acidic barrier to infection.