Phaeohyphomycosis is a rare opportunistic fungal infection. To assess the range of clinical presentations and outcomes of phaeohyphomycosis in patients with cancer, we reviewed cases diagnosed at the M. D. Anderson Cancer Center (Houston, TX).We searched the microbiology laboratory records for dematiaceous molds that had been isolated during the period from January 1989 through March 2008. Demographic and clinical data were abstracted from patients' medical records. Invasive phaeohyphomycosis was defined according to the criteria of the European Organization for Research and Treatment of Cancer Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycosis Study Group for proven or probable invasive fungal disease. Archived dematiaceous mold isolates were tested for antifungal drug susceptibility.Of 348 isolates of dematiaceous fungi recovered, only 39 isolates (11%), recovered from 39 patients, were associated with proven or probable invasive fungal disease (33 proven and 6 probable). The incidence rate of phaeohyphomycosis increased from 1.0 to 3.1 cases per 100,000 patient-days during the study period (P = .006). Of these 39 patients, 14 (36%) had a breakthrough infection while receiving prophylactic or empirical antifungal therapy. Sites of infection were the lungs (15 [38%] of 39 patients), skin (15 [38%]), sinuses (14 [36%]), and bloodstream (7 [18%]). Thirteen patients (33%) had a disseminated infection. Values of the serum galactomannan index were measured for 11 (28%) of 39 patients. The galactomannan index value was elevated (>0.5) in 5 (45%) of these 11 patients. The mortality rate at 12 weeks was 33%. Cox regression analysis revealed a significantly higher risk of death for patients with disseminated infection (hazard ratio, 5.7; P = .03) and a lower risk for patients who recovered from neutropenia within 30 days (hazard ratio, 0.2; P = .04). Isolates were frequently not susceptible to voriconazole and caspofungin.Although rare, dematiaceous molds are increasingly encountered in immunosuppressed patients with cancer. The propensity of these fungi for dissemination and for resistance to antifungal drugs presents management challenges.