A reduction in the plasma zinc concentration is a well-recognized complication of hemodialysis. A positive clinical response to zinc therapy under controlled conditions is the most reliable criterion of zinc deficiency. Zinc therapy using a nonproprietary zinc dialysate was evaluated in 12 dialysis patients with proven hypogeusia and polyneuropathy, in a randomized double-blind crossover comparison (preliminary phase, 4 weeks; placebo phase, 12 weeks; initial phase, 12 weeks; final phase, 6 weeks; post phase, 4 weeks). The dosage was related to the zinc plasma and erythrocyte levels, measured weekly. Nerve conduction velocity (NCV) and taste-testing were used to evaluate the effect of treatment at the end of the placebo and therapy phases. There was significant reduction in the recognition and determination threshold level for each of the four qualities of taste. The NCV improved significantly. The plasma zinc level could be elevated in all patients to the desired concentration, using individualized supplementation of dialysate with zinc. The erythrocyte zinc level remained constant, at double the normal value. The plasma zinc concentration fell back to the initial level 6 weeks after conclusion of therapy. We conclude that (1) zinc substitution may provide a specific therapy for uremic polyneuropathy, (2) the observed hypogeusia results from zinc deficiency, (3) long-term therapy is necessary to obtain a constant normal plasma zinc concentration, (4) zinc substitution by dialysate is a suitable and nonstressful method of administration.