Twenty-two patients with liver metastases received 45 courses of recombinant tumor necrosis factor (rTNF) by hepatic arterial infusion in doses ranging from 12.5 to 175 micrograms/m2/d for 5 days by continuous infusion. The induction of statistically significant, dose-related, severe, albeit transient, hypophosphatemia (less than 1.0 mg/dl) associated with clinically significant, right-sided myocardial dysfunction and severe lassitude was observed. These side effects were promptly reversed after rTNF was stopped and intravenous phosphate supplementation was started. As no significant or consistent increase in urinary phosphate excretion was detected, the rTNF-induced hypophosphatemia probably resulted from an intracellular shift of phosphate. Since tumor regression was clearly associated with the lowest levels of serum phosphate, hypophosphatemia may be important in the antitumor effects of rTNF.