Hematogenous candidiasis adds substantially to the morbidity and mortality rates of patients with cancer. Little is known about the risk factors and outcome in patients with breakthrough (BT) candidemia while on systemic antifungal therapy. All 479 episodes of candidemia in 474 consecutive patients with candidemia that was diagnosed at M. D. Anderson Cancer Center from 1988 through 1992 were studied retrospectively. A total of 49 patients had BT candidemia, defined as candidemia that developed after at least 5 days of systemic antifungal therapy. Risk factors for BT candidemia and predictors of mortality were investigated. Multivariate analysis revealed that intensive care unit stay, neutropenia, use of corticosteroids, and duration of neutropenia as significant risk factors for BT candidemia. Seventy-six percent of patients with BT candidemia died, compared with 50% of patients with non-BT infection. In multivariate analysis, intensive care unit stay, being and remaining neutropenic, APACHE III score, and disseminated disease were independent prognostic factors. In conclusion, identification of risk factors and predictors of a poor outcome in patients with cancer with BT candidemia may have important implications in early diagnosis and appropriate therapy of these patients.