Inactivation of the PTEN/MMAC1 tumor suppressor gene has been linked to tumor progression in several human malignancies. However, the role of PTEN/MMAC1 in the development and progression of the major renal cell carcinoma morphotypes remains controversial. We examined microdissected specimens from 80 conventional (clear cell) renal cell carcinomas (cRCC), 27 papillary renal cell carcinomas (pRCC), and 16 chromophobe renal cell carcinomas (chRCC) for loss of heterozygosity (LOH) at and around the PTEN/MMAC1 locus and for mutations in the PTEN/MMAC1 gene. The results of the molecular studies were correlated with tumor stage, grade, and patient survival. LOH at one or more of the examined loci occurred in 37.5% of cRCC, 29.6% of pRCC and 87.5% of chRCC specimens. The chRCC specimens showed increasing rates of LOH the further that a marker was located toward the q telomer of chromosome 10, consistent with nonspecific genetic disarray in genomically highly unstable tumors. No such pattern was discernible in the cRCC and pRCC. In the cRCC, LOH at intragenic PTEN/MMAC1 microsatellite markers (indicating deletional events involving the actual PTEN/MMAC1 gene) was significantly associated with tumor death, with 85.7% of such patients dying, whereas only 45.3% of patients without intragenic LOH died (P =.018). There were no PTEN/MMAC1 mutations in our specimens. We conclude that PTEN/MMAC1 inactivation may play a role in the progression of cRCC. Biallelic inactivation may preferentially occur by nonmutational mechanisms, or, alternatively, haploinsufficiency of PTEN/MMAC1 may be sufficient to affect tumor progression in cRCC.