Compensatory renal function and sodium [125I]iothalamate clearance were studied in 4 adult Merino ewes. Renal clearances of inulin (CIN), iothalamate (CIOT), and p-aminohippurate (CPAH) were used to measure renal function before and 7 and 170 days after 50% and 75% reductions in renal mass. Renal mass reduction to 50% of normal was achieved by ligation of the right renal artery, and to 25% of normal by ligating the right renal artery and branches of the left renal artery. Renal function (CIN and CPAH) after 50% renal mass reduction was 78% of normal on postligation day (PLD) 7 and 64% of normal on PLD 170. This decrease in renal function between PLD 7 and 170 was significant (P less than 0.05). Renal function (CIN and CPAH) after 75% renal mass reduction was 55% of normal on PLD 7 and 48% on PLD 170; however, this decrease in renal function between PLD 7 and 170 was not significant. Results indicated that, shortly after 50% renal mass reduction by renal arterial ligation, renal function in ewes was greater than that previously reported after unilateral nephrectomy and that a further decrease in renal function developed within 6 months after ligation. The mean CIOT in healthy ewes was 2.46 ml/min/kg of body weight. In healthy ewes and in ewes after renal mass reduction, regression of the simultaneous CIOT and CIN was CIOT = 0.276 + 1.05 CIN. The CIOT was higher than the corresponding CIN, and remained significantly (P less than 0.01) and consistently higher. Therefore, iothalamate can be used to estimate glomerular filtration rate in sheep, although a correction factor is required.