Hereditary kidney cancer syndromes predispose patients to multifocal, bilateral and/or recurrent renal tumors, requiring repeated interventions over a lifetime. Despite nephron-sparing surgery being the preferred management strategy, some patients ultimately require completion nephrectomy—radical nephrectomy following prior ipsilateral partial nephrectomy—when tumor burden, declining renal function, surgical complications, or pre-transplant indications necessitate definitive kidney removal. Data on outcomes in this population remain limited. We evaluated a prospectively maintained cohort of 58 patients who underwent completion nephrectomy at the National Institutes of Health between 2000 and 2024, following at least one prior ipsilateral partial nephrectomy. Perioperative complication rates and renal functional change were the primary outcomes of interest. Von Hippel–Lindau disease was the most common hereditary diagnosis (62.1%). Open surgery was performed in 56.9% of cases. Overall complications occurred in 43.1% of patients, with 24.1% experiencing a Clavien–Dindo grade ≥ 3 event; perioperative mortality was 6.9%. The median preoperative estimated glomerular filtration rate was 72 mL/min/1.73 m², declining to 50 mL/min/1.73 m² at the first postoperative clinic visit. Completion nephrectomy in hereditary kidney cancer syndrome patients is associated with substantial perioperative morbidity, mortality, and expected renal functional decline. These findings inform patient counseling and surgical decision-making in this high-risk population.