A phase I trial was initiated to establish the dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of chronomodulated 5-fluorouracil and cisplatin given concurrently with preoperative radiotherapy in patients with esophageal cancer. Patients with stage I or II esophageal cancer received preoperative radiation therapy (28-30 daily 1.8-Gy fractions for a total of 50.4 or 54 Gy) and concurrent three fortnightly cycles of chronomodulated 5-fluorouracil (700-835 mg/m2 per day, d1-d4, with peak delivery at 4.00 am) and cisplatin (50 mg/m2, d1, with peak delivery at 4.00 pm) administered by a time-programmable pump. Ten patients were treated on this study. Two of six patients treated at the starting dose-level experienced acute DLTs (esophagitis, asthenia) which required de-escalation of 5-fluorouracil. Five patients out of ten experienced seven DLTs (severe esophagitis, asthenia, vomiting: 5/1/1) at any dose-level. The MTD was not assessed because the study was halted due to slow accrual. Finally, two patients deceased from an Acute Respiratory Distress Syndrome due to inadequate radiation therapy planning. Without definitively ruling out any possible impact of chronomodulation in that setting, our data reinforce the need of a better selection of patients aimed to be treated by CRT plus surgery.