Background: Serious infectious complications (SICs), frequently observed morbidities, have been reported to be related not only with short-term mortality but also with poor long-term survival in various types of malignancies including esophageal cancer. SICs usually develop 7 to 10 days after esophagectomy and early diagnosis is believed to be difficult because systemic response by SICs is considered to be covered by surgical invasion. The aim of this study was to investigate whether serum C-reactive protein (CRP) on postoperative day (POD) 4 can be predictor of SICs after esophageal cancer surgery. Methods: The present study retrospectively examined 110 consecutive patients undergoing open thoracic esophagectomy after neoadjuvant chemotherapy for thoracic esophageal cancer between January 2011 and June 2015. All patients received perioperative care of enhanced recovery after surgery program with steroid therapy. SICs were defined as morbidity of grade III or more according to the Clavien-Dindo classification. Diagnostic accuracy was determined by measuring the area under the receiver operating characteristic curve (AUC). Clinical and laboratory parameters including CRP, all available before or within POD 4, were analyzed with univariate and multivariate logistic regression model to identify SICs. Results: Median age was 68 years. SICs were observed in 20 patients (18.2%). CRP on POD 4 had superior diagnostic accuracy for PICs (AUC 0.759; 95% confidence interval [CI], 0.652-0.866). Cut-off value for CRP was determined as 4.0 mg/dl which yielded a sensitivity of 70.0%, a specificity of 74.4% and a negative predictive value of 91.8% for the detection of SICs. Multivariate analysis identified CRP ≥ 4.0 mg/dl on POD 4 (odds ratio of 8.399 with 95% CI, 2.646–26.666) and three-field lymph node dissection (odds ratio of 4.658 with 95% CI, 1.306–16.619) as predictive factors for SICs after esophagectomy. Conclusions: CRP on POD 4 was an early indicator for serious infectious complications after esophageal cancer surgery, which could encourage imaging study to detect the focus or early intervention by antibiotics.