Evolutionary rates of sites can be independent of one another or correlated in some fashion. Significant spatial autocorrelation was observed for site amino acid replacement rates in vasopressin receptor family proteins (VPRs). Spatial autocorrelation of rates is the propensity of residues to lie near other residues of similar rate in the folded protein structure. Optimal correlation occurred at a distance suggesting that residues in contact had correlated rates. As another way to study the same phenomenon, VPR was partitioned into >40 x 10 A(3) contiguous spatial clusters for amino acid replacement rate estimation. Partitioning was done without preconception of functional regions of the protein and with a random partition control. Cluster rates exhibited an overdispersed distribution suggesting that rates were not randomly distributed in the spatial partitions. In tests, cluster partitioning improved maximum likelihood and Bayesian likelihood models for VPR evolution. Spatial clusters with outlier rates, or lineage-specific clusters differing in rate, proved to contain VPR features likely to be under selection. Thus the spatial autocorrelation observed is probably not just a statistical finding, but likely has an evolutionary basis in protein function.