Previously reported haploid genome sizes (C-values) and erythrocyte sizes (measured as mean dry diameters) were compared for 67 species of mammals representing 31 families and 16 orders. Measurements on erythrocytes of four species of bats were also included in the study. Erythrocyte size was significantly positively correlated with genome size at each of the specific, generic, familial, and ordinal levels, with the relationship becoming much stronger following the exclusion of the order Artiodactyla, a group unique among mammals in terms of red blood cell morphology. Physiologically, these results are relevant in light of the known relationship between C-value and mass-corrected metabolic rate in homeotherms. In evolutionary terms, they provide insights into the constraints on genome expansion among mammals and are therefore of interest in attempts to solve the long-standing C-value enigma (also known as the C-value paradox).