Reports of blastomycosis in individuals infected with the human immunodeficiency virus (HIV) are increasing. We report on 3 patients co-infected with blastomycosis and HIV (to add to the previously reported 21), and review important clinical aspects and outcomes in all cases. The percentage of patients co-infected with blastomycosis and HIV who had disseminated blastomycosis (63%) was similar to the blastomycosis patients in the general population (67%); however, as a group the patients with HIV were severely immunosuppressed and fared poorly. Severe immunodeficiency was indicated by CD4 counts < 200/mm3 in 85% of co-infected patients. Central nervous system (CNS) involvement occurred in 46% of this group, approximately 5 to 10 times more frequently than in individuals not infected with HIV previously reported at 5% to 10%. The mortality rate from blastomycosis for patients with both HIV infection and blastomycosis is 54%, about 5 times the mortality rate of blastomycosis patients in the general population, previously reported at < 10%. Disseminated blastomycosis in individuals with HIV may appear as deep cutaneous ulcers, as was the case in two of our patients. Although blastomycosis is not an AIDS-defining infection, it may be reasonable to consider HIV testing and measurement of CD4 counts in patients with blastomycosis. Such testing could help identify individuals who are HIV positive but asymptomatic who have blastomycosis, as well as provide useful information regarding a possible association between CD4 cell deficiency and various clinical manifestations of blastomycosis. Patients with HIV and blastomycosis should be examined carefully for any evidence of CNS involvement. Lifetime therapy with ketoconazole or itraconazole is likely to be of benefit to patients with HIV who have been treated successfully for blastomycosis.