Renal involvement in von Hippel-Lindau (VHL) disease has emerged as the most prevalent cause of death in this hereditary disorder. In a group of 43 VHL patients (23 unrelated families) with renal lesions we examined whether severity of renal disease is affected by parental inheritance and VHL subtype (1, without pheochromocytoma; 2, with pheochromocytoma). We also tested whether and how nephron-sparing surgery could be applied. Renal involvement comprised multiple cysts and bilateral and multifocal carcinomas (RCC) which were detected by screening in 38 patients, at 30.5 (14 to 62) years of age. The severity of the renal disease was similar in VHL type 1 (79% of the pedigrees) and 2 (21%). It was not influenced by the sex of the carrier. Twenty-nine patients were operated on at a mean age of 33.6 years: 21 patients (28 kidneys or 61% of all operated kidneys) underwent nephron-sparing surgery, 4 had complete ablation of involved kidneys and thus required dialysis, 3 had uninephrectomy and 1 had cyst fenestration. Vascular thrombosis was the most severe early complication. It occurred in 4 of 9 kidneys treated by ex vivo surgery. During a median follow-up of 29 months, local recurrence occurred in 5 of 21 (24%) patients treated by nephron-sparing surgery, whereas 2 developed metastasis. Chronic renal failure (creatinine > 120 mumol/liter) affected 11 patients; in 9 of them, it was due to sequelae of surgery. In conclusion, screening of RCC and nephron-sparing surgery are of value in VHL patients. However, indications of ex vivo surgery should be drastically restricted and renal sequelae are not uncommon. Renal followup is required because of the risk of recurrence.