Objective: The aim of the study was to evaluate whether normoalbuminuric type 1 diabetic patients with diabetic retinopathy (DR) have an impaired tubular response to desmopressin (dDAVP, a synthetic analog of vasopressin) administration, and its relationship with plasma and urine endothelin-1 (ET-1) levels. Design: This was an interventional case-control study. Setting: The study was conducted at a referral center. Participants: Fifteen normoalbuminuric type 1 diabetic patients with DR were compared with 30 normoalbuminuric type 1 diabetic patients without DR. Both groups were matched by age, gender, body mass index, glycosylated hemoglobin, and the main laboratory markers of kidney function. Intervention: After a 12-h period of water deprivation, dDAVP (0.3 μg/kg) was infused over 20 min. Urine was collected at baseline and 1, 2, and 3 h after dDAVP administration. ET-1 was assessed by ELISA. Results: dDAVP induced a lower rise in urine osmolality in patients with DR (from 650 ± 206 to 754 ± 224 mosmol/kg; P = 0.02) than in diabetic patients without DR (from 714 ± 194 to 905 ± 163 mosmol/kg; P < 0.0001). In addition, fractional excretion of Na+ decreased in patients without DR (from 0.45 ± 0.30 to 0.29 ± 0.29%; P = 0.04) but not in the diabetic patients with DR (from 0.36 ± 0.22 to 0.36 ± 0.40%; P = 0.96). Plasma ET-1 levels were inversely correlated with the response of urinary osmolality after dDAVP administration (r = -0.62; P = 0.008). Conclusions: Normoalbuminuric type 1 diabetic patients with DR have impaired renal response to dDAVP that is related to plasma ET-1 levels. Further studies are required to elucidate whether this tubular resistance to dDAVP might favor dehydration in these patients. Copyright © 2009 by The Endocrine Society.