This study presents a whole–genome comparison of human and a representative of the Afrotherian clade, the African elephant, generated by reciprocal Zoo–FISH. An analysis of Afrotheria genomes is of special interest, because recent DNA sequence comparisons identify them as the oldest placental mammalian clade. Complete sets of whole–chromosome specific painting probes for the African elephant and human were constructed by degenerate oligonucleotide–primed PCR amplification of flow–sorted chromosomes. Comparative genome maps are presented based on their hybridization patterns. These maps show that the elephant has a moderately rearranged chromosome complement when compared to humans. The human paint probes identified 53 evolutionary conserved segments on the 27 autosomal elephant chromosomes and the X chromosome. Reciprocal experiments with elephant probes delineated 68 conserved segments in the human genome. The comparison with a recent aardvark and elephant Zoo–FISH study delineates new chromosomal traits which link the two Afrotherian species phylogenetically. In the absence of any morphological evidence the chromosome painting data offer the first non–DNA sequence support for an Afrotherian clade. The comparative human and elephant genome maps provide new insights into the karyotype organization of the proto–afrotherian, the ancestor of extant placental mammals, which most probably consisted of 2n = 46 chromosomes.