Arabidopsis thaliana is believed to have experienced at least two and possibly three whole-genome duplication events in its evolutionary history. In order to investigate the evolutionary relationships between these duplication events and diversification of disease resistance (R) genes, segmental-duplication events containing R genes belonging to the nucleotide binding-leucine rich repeat (NB-LRR) class were identified. Of 153 segmental-duplication events containing NB-LRR genes, only 22 contained NB-LRR genes in both members of the duplication pair, indicating a high frequency of NB-LRR gene loss after whole-genome duplication. The relative age of the duplication events was estimated based on the average synonymous substitution rate of the duplicated gene pairs in the segments. These data were combined with phylogenetic analyses. NB-LRR genes present in segment pairs derived from the most recent whole-genome duplication event, estimated to have occurred only 20 to 40 million years ago, occupy very distant branches of the NB-LRR phylogenetic tree. These data suggest that when NB-LRR clusters are duplicated as part of a whole-genome duplication, homoeologous NB-LRR genes are preferentially lost, either by eliminating one copy of the cluster or by eliminating individual genes such that only paralogous NB-LRR genes are maintained.