Hyperthermic isolated limb perfusion (HILP) with recombinant tumor necrosis factor-α (r-TNFα) and melphalan has been shown to result in a sepsis-like syndrome due to leakage of r-TNFα from the perfusion system to the systemic circulation. We have studied renal function parameters in 11 cancer patients, who underwent 12 perfusions. Three patients, perfused with melphalan only, served as controls. All patients treated with r-TNFα developed a sepsis syndrome and needed volume replacement and inotropes to remain normotensive; controls had an uneventful postoperative course. Creatinine clearance decreased transiently on the day of perfusion in both groups (mean preperfusion clearance 118 ml/min, mean post-perfusion clearance 68 ml/min, p < 0.02, n = 15). Follow-up measurements of renal plasma flow and glomerular filtration rate in 9 r-TNFα-treated patients did not suggest permanent damage. One patient became hypotensive and developed transient multiple organ dysfunction with renal failure needing hemofiltration. In r-TNFα-treated patients, but not in controls, a transient increase in clearance of β2-microglobulin (0.05 vs. 8 ml/min, p < 0.001) and urinary excretion of phosphate (12 vs. 48 mmol/l, p < 0.05) was seen, compatible with proximal tubular dysfunction. These data suggest that HILP with melphalan decreases glomerular function, whether or not r-TNFα is added to the perfusion circuit. Extension of the treatment regimen with r-TNFα may result in additional proximal tubular dysfunction. If hypotension can be avoided, this deterioration in renal function seems to be transient, with full recovery within weeks.