To elucidate the mechanism of cyclophosphamide (CTX)-induced antidiuresis, plasma and urine volume as well as serum electrolytes, creatinine, osmolality, and appropriate hormones were monitored serially during 19 courses of chemotherapy. In spite of plasma hypotonicity and urinary hypertonicity, the plasma vasopressin concentrations were unaltered. Intravenous isotonic hydration did not prevent water retention, but did not lead to plasma hypotonicity, and compensated for modest urinary sodium losses. Furosemide diuresis did not prevent the development of hyponatremia in patients receiving hypotonic hydration. The results indicate that the origin of this self-limited syndrome is a direct effect of CTX on the renal tubule, permitting increased water reabsorption and sodium loss. The likelihood that water and salt imbalance will develop after CTX administration can be reduced by vigorous isotonic hydration, and pharmacological diuresis.