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Background: Although intralesional vinblastine has been used with some success in the treatment of cutaneous lesions of Kaposi's sarcoma (KS), lesions commonly recur. When large lesions are treated, frequently there is considerable discomfort and, in some cases, secondary ulceration. Hyaluronidase has been used to increase dispersion of drugs administered by local injection. Objective: Our purpose was to determine whether intralesional hyaluronidase administered before intralesional vinblastine increases the dispersion of vinblastine and decreases toxicity. Methods: We treated six patients who had multiple cutaneous plaque lesions and tumors of KS with intralesional vinblastine, intralesional vinblastine preceded by intralesional hyaluronidase, or intralesional hyaluronidase alone. Results: Both intralesional vinblastine and intralesional vinblastine preceded by intralesional hyaluronidase caused clinical regression of lesions of KS; however, the combination of hyaluronidase and vinblastine was more effective in treating tumor nodules. In addition, lesions treated with hyaluronidase and vinblastine recurred less often than those treated with vinblastine alone and showed no evidence of residual KS in two patients undergoing biopsy between 4 and 6 months after therapy. Conclusion: Intralesional hyaluronidase enhances vinblastine in the treatment of cutaneous lesions of KS without adding to the systemic toxicity. (J Am Acad Dermatol 1997;36:239-42.)