The charge isomers of human GH (/GH), isohormones C, D, and E, which result from limited proteolytic cleavage exhibit enhanced biological activity in the rat and in man compared to the intact polypeptide and most abundant form, isohormone B. The mechanism leading to enhanced activity is unknown. To examine the possibility that different in vivo metabolism may represent one such mechanism, the MCRs of radioiodinated hGH-B, -C, and -D were measured in seven normal adults. Significant differences in metabolic clearance were found between isohormones (hGH-B, 108.4; hGH-C, 67.9; hGH-D, 55.7 liters/m2-day). It is concluded that in man, the enzymatically cleaved hGH isohormones are cleared more slowly than hGH-B. Slower metabolism may be a factor responsible for the enhanced biological activity of proteolytically cleaved hGH isohormones.