We have studied the sequential effects of cyclosporine during the first four days after its initiation in an effort to elucidate the primary and secondary events in the pathogenesis of cyclosporine induced nephrotoxicity and hypertension. Knowledge about the earliest effects of cyclosporine provides a more logical approach for devising therapeutic strategies to counteract nephrotoxicity and hypertension. On day 1, cyclosporine acutely increased systemic BP and decreased urine volume. Plasma renin activity was suppressed by day 2 and remained so thereafter. Renal sodium excretion was not affected until day 4 at which point a natriuresis occurred. Cyclosporine exerted a more marked antidiuretic effect on day 4 compared to day 1, which was augmented by a physiological infusion of vasopressin. Over the first four days of therapy, glomerular filtration rate and effective renal plasma flow were unchanged. Our data show that cyclosporine induced hypertension in the initial stages is not sodium dependent, and that changes in renal water handling were not dependent on alterations in the glomerular filtration rate or effective renal plasma flow. In fact, a natriuresis occurred which was most likely due to a combination of pressure natriuresis and angiotensin II suppression. The cyclosporine induced antidiuresis may indicate a distal nephron effect since cyclosporine augmented the antidiuretic effect of vasopressin, although vasopressin levels per se were not increased by cyclosporine alone.