Context.—Kaposi sarcoma (KS) is a vascular tumor frequently associated with advanced human immunodeficiency virus infection, advanced age, or iatrogenic immunosuppression. Immunohistochemistry for CD31 and CD34, and more recently for FLI1 and D2-40, has been used as ancillary diagnostic tests for KS, despite little information regarding the sensitivities and differential staining patterns of the latter 2 markers in the major clinical subtypes and histologic stages of KS. Objective.—This retrospective study aims to assess the prevalence of the vascular markers D2-40 and FLI1 in the main clinical subgroups and tumor stages of KS. Design.—Twenty-four cases of KS (12 acquired immunodeficiency syndrome [AIDS]–related cases and 12 non–AIDS-related cases; 11 nodular-stage and 13 patch/plaque–stage KS) were stained for CD34, CD31, D2-40, and FLI1 by immunohistochemistry. The distribution of immunoreactivity was compared between the clinical subtypes and tumor stages of KS using the Mann-Whitney test. Results.—CD31, CD34, D2-40, and FLI1 strongly and diffusely stained tumor cells in 75%, 92%, 67%, and 92% of AIDS-related cases and 58%, 92%, 67%, and 75% of non–AIDS-related cases, respectively. Differences in the proportions of positive cases between AIDS-related and non–AIDS-related cases did not reach statistical significance. No significant staining differences were observed between nodular- and patch/plaque–stage KS either. Conclusions.—There are no differences in the distribution of immunohistochemical reactivity for CD31, CD34, D2-40, or FLI1 between AIDS-related and non–AIDS-related KS or between nodular- and patch/plaque–stage KS. All of the markers studied demonstrated high sensitivity in both clinical settings and both stages of tumor progression.