Despite evidence that prostate cancer has a genetic etiology, it has been extremely difficult to confirm genetic linkage results across studies, emphasizing the large extent of genetic heterogeneity associated with this disease. Because prostate cancer is common--approximately one in six men will be diagnosed with prostate cancer in their life--genetic linkage studies are likely plagued by phenocopies (i.e., men with prostate cancer due to environmental or lifestyle factors), weakly penetrant alleles, or a combination of both, making it difficult to replicate linkage findings. One way to account for heterogeneous causes is to use clinical information that is related to the aggressiveness of disease as an endpoint for linkage analyses. Gleason grade is a measure of prostate tumor differentiation, with higher grades associated with more aggressive disease. This semi-quantitative score has been used as a quantitative trait for linkage analysis in several prior studies. Our aim was to determine if prior linkage reports of Gleason grade to specific loci could be replicated, and to ascertain if new regions of linkage could be found. Gleason scores were available for 391 affected sib pairs from 183 hereditary prostate cancer pedigrees as part of the PROGRESS study. Analyzing Gleason score as a quantitative trait, and using microsatellite markers, suggestive evidence for linkage (P-value <or= 0.001) was found on chromosomes 19q and 5q, with P-values <or= 0.01 observed on chromosomes 3q, 7q, and 16q. Our results confirm reports of Gleason score linkage to chromosome 19q and suggest new loci for further investigation.