Phylogenetic methods were used to analyze cytochrome-b sequences (n = 257; 560 base pairs) from Peromyscus keeni (Keen's mouse) collected from 23 islands of the Alexander Archipelago and 6 mainland locations in southeast Alaska and western Canada. Although P. keeni is ubiquitous across this region, island populations are genetically distinctive. Genetic structure of extant populations of P. keeni appears to have been more heavily influenced by vicariance than post-glacial colonization. Populations of P. keeni might have survived in coastal refugia during the last glacial maximum (15 × 10³ years ago). Island area was significantly correlated with 2 of 3 genetic diversity measures whereas island isolation was not. Areas with divergent populations were discovered, but were largely inconsistent with 3 of 5 currently recognized subspecies. Cryptic variation was detected in 8 areas not previously identified by morphologic analyses.