Patients with esophageal cancer are at high risk of developing malnutrition during neoadjuvant chemoradiation therapy (CRT), which in turn is associated with postoperative morbidity. The aim of the study is to explore whether parameters of a complete pre-treatment nutritional status may predict deterioration of nutritional status during CRT in patients with esophageal cancer. In this prospective cohort study, 101 patients with esophageal cancer treated with CRT were included. Data of patient characteristics, tumor classification, performance score, %weight change, body mass index, fat (free) mass index, phase angle, handgrip strength, energy- and protein intake, and use of (additional) dietary supplements were collected. A prediction model was constructed to identify predictive parameters for deterioration in nutritional status (defined as weight loss of >5% and/or decline in fat free mass of ≥1.4 kg) during CRT. Nutritional status deteriorated in 49 patients (49%) during CRT. The only predictor for deterioration in nutritional status was fat free mass index (OR 1.21 (90% CI: 1.03–1.42)). Patients with a higher fat free mass index are at increased risk of deterioration in nutrition status during CRT. Results suggest that all patients should be carefully supervised during CRT, regardless of their nutritional status before start of CRT.