To further define the genetic events that could lead to the development of borderline ovarian tumors (BOTs), we analyzed 13 microsatellite markers on chromosomes 3p and q in 18 BOTs and compared the results to 31 serous invasive epithelia] ovarian cancers (IEOCs). Five of the 18 BOTs showed microsatellite instability (MSI) at one or more loci, compared to only 2 of the 31 IEOCs studied (P < 0.04). In two of these five BOTs, MSI was found in multiple loci. All BOTs with MSI were serous, while none of the mucinous type showed any alteration. Loss of heterozygosity was found in only 1 of the 18 BOTs, but in 12 of the 31 IEOCs (P < 0.01). This first report of a relatively high percentage of MSI in BOTs opens a wide spectrum of new hypotheses for borderline ovarian tumorigenesis as well as several new research avenues.