Since the demonstration that β₂-microglobulin (β₂M) is an amyloidogenic protein in man, the excretion of this low-molecular-weight protein under conditions with normal and reduced function has received increased interest. The renal arteriovenous extraction of β₂M, polyfructosan (an inulin analogue), and a second low-molecular-weight protein, myoglobin, was measured in vivo in 16 human kidneys with normal renal function/gross morphology and in 22 kidneys with reduced function. In kidneys with normal function, the extraction of β₂M significantly exceeded that of polyfructosan (0.198 ± 0.037 vs 0.182 ± 0.05; p = 0.04), while that of myoglobin (0.177 ± 0.068) was not different from that of polyfructosan. In kidneys with reduced function, the extraction of polyfructosan or myoglobin was not significantly altered. In contrast, the β₂M extraction decreased to 0.110 ± 0.060 (p<0.01 vs. extraction of polyfructosan or myoglobin). This decrease was significantly correlated with the decrease of the endogenous creatinine clearance or the total or unilateral ¹³¹I-hippuran clearance. These results indicate that in normal renal function the glomerular filtration of β₂M may be supplemented by a peritubular mode of removal. The mechanisms(s) underlying the selective decrease of β₂M extraction in kidneys with reduced function remain speculative. However, this decrease will lead to a further augmentation of the retention of β₂M in renal failure.