Abstract Background 15–20% of ulcerative colitis (UC) patients will eventually undergo total proctocolectomy (TPC) with or without a restorative pouch following. The two main indications include refractory UC and advanced colonic neoplasia. Risk factors associated with TPC in the biological era are not clarified. The aim of the study was to compare TPC performed with a finding of neoplasia to all other indications. Methods An observational retrospective analysis of all TPC performed at a single tertiary referral medical center between 2003–2020, was performed. Results Seventy-nine patients were included, 25 (31%) with neoplasia and 54 (69%) for all other indications. Average age was 42, 62% men, and 12.5 years of disease prior to surgery. Out of the neoplasia group, only 6 (24%) and 8 (32%) were exposed to biologics and steroids prior to surgery, opposed to 36 (66.6%) and 38 (70%) in the controls, p=0.005 and 0.001 respectively. Average years of disease was 18.7± 13 for neoplasia group compared to 9.7± 11 years for the controls, p<0.001. The major indications for TPC in the neoplasia group were a finding in colonoscopy 16 (64%) and treatment failure 5 (20 %), opposed to 4 (7%) and 43 (80%) in the controls, p<0.001 for both, respectively. Short term complications and long term complications occurred in 15 (60%) and 6 (24%) of in the neoplasia group compared to 39 (72%) and 33 (61%) in the controls, p=0.27 and 0.002, respectively. Hemoglobin was higher and albumin lower in the neoplasia group. Two-step procedures and three-step procedures were performed on 12 (48%) and 1 (4%) of patients in the neoplasia group compared to 27 (50%) and 16 (29%) in the controls, p=0.86 and 0.01, respectively. Conclusion Even in the biologic era, neoplasia encounters nearly one-third of TPC procedures. Short disease duration and use of biologics are correlated with a decreased risk for neoplasia. Long term complications are less common when TPC performed due to neoplasia.