Multiple endocrine neoplasia (Menl) is an autosomai dominant hereditary trait characterized by tumors of endocrine tissues. The MEN1 gene maps to chromosome llql3, has been recently isolated, and encodes a protein termed menin that is ubiquitously expressed. This gene is likely to be a tumor suppressor gene, with tumors developing after the inactivation of both copies of the gene in a single cell. In agreement with this, 11q-deletions (loss of heterozygosity) are frequently found in neoplasms from MEN1 patients. In this study, DNA from family-members was extracted and analysed for 10 microsatellites flanking the MEN1-gene on chromosome 11q. SSCP was used to determine the presence of MEN1-mutations in several patients. DNA was extracted from paraffin blocks containing tissue from 10 parathyroid tumors (4 familial and 6 sporadic) and 2 gastrinomas (both from patients of the Men1-family). LOH was determined by comparing the autoradiographic patterns of several markers between the normal tissue and the malignant tissue counterpart. All the affected individuals in the MEN1-family shared one haplotype, not present in the healthy individuals. We searched for mutations at the MEN1 gene (SSCP-analysis) in several affected members. An SSCP-mobility shift was found at exon 9, and direct sequencing showed that this corresponded to a common polymorphism at codon 418 (GAC/GAT), LOH, a genetic alteration characteristic of genomic regions containing tumor suppressor genes, was found in all the parathyroid tumors, but not in two gastrinomas. SSCP-analysis of the MEN1-exon 9 polymorphism showed that LOH included the MEN1-gene in the informative parathyroid tumors. In conclusion, LOH at 11q is frequent in Menl-parathyroid tumors, either sporadic or familial, and the deletion involves the MEN1-gene. In contrast, the two gastrinomas did not show LOH, indicating the existence of a second mutation other than the MEN1-deletion in these tumors. Our data suggest that the mechanism that drives tumorigenesis in Menl either familial or sporadic, is influenced by the tissue context.