Humans and larger mammals require more blood cells per lifetime than mice because of their larger size and longer life expectancy. To investigate this evolutionary adaptation, we calculated the total number of nucleated marrow cells (NMCs) per cat, observing the distribution of (59)Fe to marrow, then multiplied this value (1.9 +/- 0.9 x 10(10) [mean +/- SD]) times the frequency of feline hematopoietic stem cells (HSCs) (6 HSCs/10(7) NMCs) to derive the total number of HSCs per cat (11 400 +/- 5400). Surprisingly, when the total number of HSCs per mouse was calculated with a similar experimental and computational approach, the value was equivalent. These data imply that the output of differentiated cells per feline HSC must vastly exceed that of murine HSCs. Furthermore, if the total number of human HSCs were also equivalent to the total number of HSCs in cat and mouse, the frequency of human HSCs would be 0.7 to 1.5 HSCs/10(8) NMCs, a frequency that is 20-fold less than estimated by the NOD/SCID repopulating assay.