Many chromosome regions in the human genome exist in four similar copies, suggesting that the entire genome was duplicated twice in early vertebrate evolution, a concept called the 2R hypothesis. Forty-two gene families on the four Hox-bearing chromosomes were recently analyzed by others, and 32 of these were reported to have evolutionary histories incompatible with duplications concomitant with the Hox clusters, thereby contradicting the 2R hypothesis. However, we show here that nine of the families have probably been translocated to the Hox-bearing chromosomes more recently, and that three of these belong to other chromosome quartets where they actually support the 2R hypothesis. We consider 13 families too complex to shed light on the chromosome duplication hypothesis. Among the remaining 20 families, 14 display phylogenies that support or are at least consistent with the Hox-cluster duplications. Only six families seem to have other phylogenies, but these trees are highly uncertain due to shortage of sequence information. We conclude that all relevant and analyzable families support or are consistent with block/chromosome duplications and that none clearly contradicts the 2R hypothesis.