Previous cytogenetic analysis has revealed frequent losses of chromosome 1p21-22 in human malignant mesothelioma, suggesting that the loss or inactivation of a tumor suppressor gene's) residing at this site may contribute to the tumorigenic conversion of mesothelial cells. To more precisely define the location of the target gene, primary tumor specimens and cell lines from 50 malignant mesotheliomas were examined for loss of heterozygosity using short tandem repeat polymorphism (STRP) markers. Nineteen STRP markers established by the Cooperative Human Linkage Center were selected for the initial screening of the entire short arm of chromosome 1. Thirty-seven cases (74%) showed allelic losses at least at one locus in 1p. Thirty-six of these cases showed losses of 1p21-22, including 23 with partial deletions involving this region. To obtain a higher resolution map of this region, another 13 STRP markers from the Genethon map were used to define the shortest region of overlapping deletions to a 4-cM segment flanked by the loci D1S435 and D1S236. The chromosomal location of the critically deleted region was confirmed to be within 1p22 by karyotypic and fluorescence in situ hybridization analyses.