Occasionally, testicular teratomas have been observed to occur in association with somatic-type malignancies. The latter may be seen in the primary germ cell tumor or, more commonly, in metastases after chemotherapy. The molecular-genetic relationship between the teratoma and the somatic-type malignancy is uncertain. We examined 27 pairs of teratoma and somatic-type malignancies in metastatic lesions. Interphase fluorescence in situ hybridization (FISH) analysis for 12p overexpression and i(12p) was performed on formalin-fixed, paraffin-embedded specimens. In addition, we compared the pattern of allelic loss between the teratoma and the somatic-type malignancy using 4 microsatellite DNA markers (D1S508, interferon-α, D13S317, and D18S543). A laser capture microdissection technique was used to procure separate tumor components. The somatic-type malignancies included adenocarcinoma (13), primitive neuroectodermal tumor (5), sarcoma not otherwise specified (5), squamous cell carcinoma (1), chondrosarcoma (1), and rhabdomyosarcoma (2). Twenty-one of 27 tumor pairs (78%) showed a similar pattern of overexpression of 12p and/or i(12p) in both components. Two of the 27 (7%) tumor pairs showed i(12p) only in the teratomatous component, and 4 of the 27 (15%) tumor pairs showed no abnormalities of chromosome 12p by interphase FISH. Eight of the 12 (67%) tumor pairs analyzed had identical patterns of loss of heterozygosity in both the teratoma and the somatic-type malignancy. Four of the 12 (33%) paired cases showed additional allelic loss at the interferon-α locus in the somatic-type malignant component only. Our data show that the somatic-type malignancies that develop in germ cell tumors have the same genetic alterations, detectable by FISH and loss of heterozygosity studies, as in the corresponding teratoma. These findings support that the somatic-type malignancies within metastases and the teratomas are clonally related and likely derived from a common progenitor cell. Interphase FISH can be performed on formalin-fixed, paraffin-embedded tissue and is a sensitive method for detecting 12p overexpression and i(12p), thus aiding in establishing the germ cell origin of somatic-type malignancies in this context.