Primary cutaneous (PC) CD30-positive large cell lymphoma and lymphomatoid papulosis (LyP) represent the spectrum of PC CD30-positive lymphoproliferative disorders (LPDs) associated with a favorable prognosis. Noncutaneous CD30-positive anaplastic large cell lymphoma (ALCL), although morphologically similar to PC CD30-positive LPDs, seems to be a biologically distinct entity. Cell lines derived from noncutaneous ALCL express CD95 and undergo CD95-induced apoptosis. Little is known about expression or function of CD95/CD95L in cutaneous lesions. We examined a series of PC CD30-positive LPDs and noncutaneous ALCL for expression of CD95/CD95L to investigate possible differences between these histologically similar but biologically distinct entities. Paraffin-embedded, formalin-fixed tissue sections from 25 cases of CD30-positive LPDs (10 noncutaneous ALCL, 15 PC CD30-positive LPDs) were immunostained for CD3, CD20 (L26), CD43 (Leu22), CD30 (BerH2), anaplastic lymphoma kinase (ALK-1), CD95, and CD95L (C-33). One hundred large atypical cells and 100 small lymphocytes were counted to determine the percentage of CD95/ CD95L-positive cells. Statistical analysis using the Mann-Whitney U test was performed. CD95 expression was slightly higher in the large atypical cells of noncutaneous ALCL compared with PC CD30-positive LPDs (median, 100% versus 94%; P = .003) because of the lower expression of CD95 in LyP. CD95L expression was higher in the surrounding small lymphocytes in PC CD30-positive LPDs (median, 3% versus 13%; P = .002). Expression of CD95 in the small lymphocytes and CD95L in the large atypical cells was not significantly different. These results support the biologic distinction between cutaneous and noncutaneous CD30-positive LPDs and may have implications in the differing clinical behavior of these entities. Further study of expression and function of apoptosis-related proteins in these entities is warranted.