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Cancer/testis (CT) antigens are members of a large tumor-associated protein family of increasing interest because of their diagnostic and possible therapeutic implications. Only few studies have investigated CT antigen expression in Hodgkin’s lymphoma (HL) so far. Recently, immunopurification of a 25/22-kDa antigen and sequencing revealed a peptide of 14 amino acids, which corresponds to the gene product of the newly described gene family MGC27005, located on chromosome Xq26.3, now termed CT45. The antigen shows a CT antigen-like expression pattern in human tissues and is detectable by the monoclonal antibody Ki-A10 generated after immunization of mice with HL-derived cell line L428. In this study, the expression pattern of CT45 in a large number of patients with HL included in subsequent pediatric multicenter treatment protocols of the GPOH was analyzed. Immunohistochemical results of Ki-A10 staining were correlated with histological subtype, immunophenotype, clinical data and outcome. In total, 1124 children and adolescents with HL diagnosed between 1978 and 2004 were studied. Median age of the patients was 13.7 years (range, 2.2 to 19.5) and 637 patients 02(57%) were male. Classical HL (cHL) was diagnosed in 988 patients (88%) and nodular lymphocyte predominant HL (NLPHL) was seen in 136 patients (12%). The group of cHL included 683 cases of nodular sclerosis HL (NSHL), 280 cases of mixed cellularity HL (MCHL), ten cases of lymphocyte-rich cHL (LRCHL), seven cases of lymphocyte-depleted HL (LDHL) and eight cases without subclassification. Nuclear CT45 expression was found in 526 cases (47%) with striking differences among histological subtypes and unrelated to CD30, CD20 and latent EBV infection. In NLPHL, 15% of cases scored CT45 positive in contrast to 51% of cases in cHL (p CT45 expression, which is restricted to neoplastic cells in HL, is found in a significant number of children and adolescents with HL, especially in cases of NSHL, aggressive histological subtypes and advanced disease. Due to effective polychemotherapy with or without low-dose radiotherapy, CT45 status did not emerge as an adverse prognostic factor in children and adolescents with HL in this series.