Treatment of resectable esophageal cancer includes neoadjuvant chemo-radiation therapy (nCRT) followed by esophagectomy in operable patients. High-risk surgery may have been avoided in patients with a pathological complete response (pCR). We investigated the feasibility of optical coherence tomography (OCT) to detect residual cancer and radiation-induced fibrosis in 10 esophageal cancer patients that underwent nCRT followed by esophagectomy. We compared our OCT findings with histopathology. Overall, OCT was able to differentiate between healthy tissue, fibrotic tissue, and residual cancer with a sensitivity and specificity of 79% and 67%, respectively. Hence, OCT has the potential to add to the assessment of a pCR.