Antibodies against CD15, -30, and -20 are often used to support morphological diagnosis of Hodgkin's Disease (HD). The classical HD, i.e., the non-lymphocyte-predominance types, are CD15+, CD30+, and CD20- in general. However, the results for CD15 are less clear-cut in many studies, showing up to 40% of classical HD that lack positivity for this maker. Little is currently known about the relevance of antigen expression in relation to clinical outcome in HD. Therefore, the three markers were analyzed in 1751 cases from the German Hodgkin Study Group, using micro-wave epitope retrieval to optimize staining sensitivity. Eighty-three percent of the cases showed a classical immunophenotype (CD15+, CD30+, CD20-), twelve percent lacked CD15 positivity (CD15-, CD30+, CD20-), and five percent showed other combinations. For 1286 cases, clinical follow-up was available, which revealed significant differences for freedom from treatment failure (P = 0.0022) and overall survival (P = 0.0001) between cases with classical immunophenotype and CD15 negativity (CD30+, CD20-). Multivariate Cox regression using the three markers, age, sex, histology, stage, B-symptoms (fever, sweats, weight loss > 10% of body weight), hemoglobin, and erythrocyte sedimentation rate as factors showed that lack of CD15 expression in classical HD is an independent negative prognostic factor for relapses (P = 0.022) and survival (P = 0.0035). In conclusion, immunohistochemistry is able to identify classical HD cases with unfavorable clinical outcome.