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OBJECTIVES To compare cognitive outcomes of patients undergoing open radical nephrectomy (RN) and inferior vena cava (IVC) thrombectomy with versus without cardiopulmonary bypass (CBP) and deep hypothermic circulatory arrest (DHCA). PATIENTS AND METHODS A prospective, 6-month, observational study was conducted from January 2013 to December 2019 in RCC patients with level II - IV IVC thrombus undergoing RN. A battery of standardized neuropsychological tests was administrated to assess multi-domain cognitive function before surgery, 1 week, and 6 months after surgery: attention, executive functions, working memory, short-term and long-term delay recall, visuomotor speed, and verbal fluency. RESULTS Cognitive impairment was defined as a 20% reduction in at least 20% of the main variables. The primary outcome was the incidence of cognitive impairment at 6 months postoperatively and was analyzed with general linear mixed models. Twenty-six patients treated with CPB and 39 treated with non-CPB were analyzed. There were no significant differences in cognitive impairment between the two groups. The incidence of cognitive impairment at 1 week postoperatively was 38.5% in CPB group and 30.8% in non-CPB group (p=0.52), after 6 months 11.5% and 10.3% (p=1.00). Multivariate analysis indicated that the estimated blood loss (EBL) was the only risk factor associated with cognitive impairment at 1 week postoperatively. CONCLUSIONS This study showed no significant differences in postoperative cognitive function of RCC patients after open RN and IVC thrombectomy with and without CPB and DHCA. EBL was found to be associated with cognitive impairment at 6 months postoperatively.