Background: Disseminated infection with Histoplasma capsulatum and Mycobacterium avium complex (MAC) in patients with AIDS are frequently difficult to distinguish clinically. Methods: We retrospectively compared demographic information, other opportunistic infections, medications, symptoms, physical examination findings and laboratory parameters at the time of hospital presentation for 32 patients with culture documented disseminated histoplasmosis and 58 patients with disseminated MAC infection. Results: Positive predictors of histoplasma infection by univariate analysis included lactate dehydrogenase level, white blood cell (WBC) count, platelet count, alkaline phosphatase level, and CD4 cell count. By multivariate logistic regression analysis, those characteristics that remained significant included a lactate dehydrogenase value ≥500 U/L (risk ratio [RR], 42; 95% confidence interval [CI], 18.53-97.5; p < .001), alkaline phosphatase ≤300 U/L (RR, 9.35; 95% CI, 2.61-33.48; p = .008), WBC ≤4.5 x 106/L (RR, 21.29; 95% CI, 6.79-66.75; p = .008), and CD4 cell count (RR, 0.958; 95% CI, 0.946-0.971; p = .001). Conclusions: A predictive model for distinguishing disseminated histoplasmosis from MAC infection was developed using lactate dehydrogenase and alkaline phosphatase levels as well as WBC count. This model had a sensitivity of 83%, a specificity of 91%, and a misclassification rate of 13%.