Hypertonic dextrose (50% dextrose in water [D50W]) has been studied as a therapeutic agent to relieve dialysis-related muscle cramps (DMCs). We conducted a double-blind study comparing the effectiveness of 1 mL/kg of D50W with an identical volume of 5% dextrose in water (D5W) administered as an intravenous bolus. Twelve of 36 patients studied experienced DMCs. Thirty-three cramping episodes were studied. Eighteen were treated with D50W and 15 with D5W. Blood glucose levels and blood pressure were measured before infusion and at intervals to one hour. Cramp relief was graded and recorded at the same intervals. Eighty-nine percent of treatments with D50W resulted in complete relief, compared with 40% of treatments. Partial relief was obtained in 5.5% of treatments with D50W, compared with 40% relief with D5W. Twenty percent with D5W did not effect relief. In one treatment with D50W, observations were unsatisfactory to judge relief. There were no important side effects. We have shown D50W to be a safe effective treatment for DMC. Our data suggest that plasma volume contraction is important in the genesis of DMC, and that relief is related to expansion of plasma volume secondary to increased plasma osmolality.