Determination of the predictors of hypoproteinemia among cancer patients following extensive surgery may enhance their nutritional management and clinical outcome. This study evaluated the predictive factors of postoperative hypoproteinemia among cancer patients following extensive abdominal surgery. An age- and gender-matched case-control study (n = 115) was conducted among cancer patients undergoing extensive (cases; n = 81) and moderate (controls; n = 34) abdominal surgery. Case patients received total parenteral nutrition (TPN), including 3 units of fresh frozen plasma and 200 mL 5% human albumin solution, for 8 postoperative days (POD). Case patients had lower mean total serum protein (TSP) levels throughout POD 8 (F value = 13.81; P = 0.001). Despite TPN, cases had greatest mean (±SD) TSP percent change on POD 1 (-24.6% ± 13.0, vs. -12.6% ± 9.2; P < 0.0001) and did not regain preoperative levels (POD 8: -14.3% ± 12.5 vs. 6.9% ± 13.4; P = 0.006). The likelihood of hypoproteinemia in this group was greatest on POD 3 (OR = 30.57; 95% CI 5.44-171.83). Multivariate regression analyses indicated that the determinants of postoperative hypoproteinemia were age [Adjusted OR (AOR) = 1.04; 95% CI 1.00-1.08), preoperative TSP (AOR = 0.46; 95% CI 0.23-0.92), and extensive surgery (AOR = 2.65; 95% CI 1.01-6.95). Tailored nutritional support, regarding extent of surgery, preoperative TSP, and patient age are needed to deter the occurrence of postoperative hypoproteinemia and consequent adverse surgical outcome among cancer patients.