The role of the replication error-positive (RER+) phenotype in the development of specific subtypes of sporadic ovarian carcinomas was examined by screening for the presence of microsatellite instability (MI) in 47 tumors. The overall frequency of ovarian MI was 17% only. However, MI occurred in 50% of the ovarian endometrioid-type tumors, which was significantly more often than in all the other histological subtypes combined (8%). Five of the 8 RER+ tumors exhibited most marked type I instability, possibly representing a different mechanism than for the remaining type 2 tumors. The cDNA of the mutation suppression gene hMSH2, the gene most often associated with MI, was screened for alterations in 8 MI-positive and 5 MI-negative ovarian tumors. Only 3 changes were found. Complete loss of hMSH2 mRNA expression was detected in I tumor, while another expressed only an abnormal transcript containing a deletion of exon 3. One additional RER+ serous adenocarcinoma contained a rare polymorphism with a non-conservative amino acid change. One of 8 RER+ tumors showed loss of heterozygosity at the hMSH2 loci. Genetic instability, caused in part by alterations in the hMSH2 gene, may play an important role in the sporadic endometrioid subtype of ovarian tumors. Other mutator-phenotype genes may be responsible for the remaining cases of RER+ ovarian tumors.