Background: In esophageal cancer (EC) patients not eligible for surgery definitive chemoradiation (dCRT) with curative intent using cisplatinum with 5-fluorouracil (5-FU) is the standard regime. Nowadays carboplatin and paclitaxel are also often used. In this study we compared survival and toxicity rates between both regimens. Methods: This multicentre study included 102 patients treated in five centres in the North Netherlands from 1996 till 2008. Forty-seven patients received cisplatinum/5-FU and 55 patients carboplatin/paclitaxel. Results: Overall survival (OS) was not different between the cisplatinum/5-FU and carboplatin/paclitaxel group (P=0.879, Hazard Ratio [HR] 0.97 confidence interval [CI] 0.62-1.51), with a median survival of respectively 16.1 (CI 11.8-20.5) and 13.8 (CI 10.8-16.9) months. Median disease free survival (DFS) was comparable (P=0.760, HR 0.93 CI 0.60-1.45) between the cisplatinum / 5-FU group (11.1 months, CI 6.9-15.3) and the carboplatin/paclitaxel group (9.7 months, CI 5.1-14.4). Groups were comparable except clinical T-stage was higher in the carboplatin/paclitaxel group (P=0.008), but a high clinical T-stage (cT4) was not related to OS and DFS in a univariate analysis (P=0.250 and P=0.201). A higher percentage of patients completed the carboplatin / paclitaxel regimen (82% compared to 57%, P=0.01). Hematological and non-hematological toxicity (≥ grade 3) was significantly lower in the carboplatin / paclitaxel group (4% and 18%) than in the cisplatinum/5-FU (19% and 38%, P=0.001). Conclusions: In this study we show comparable outcome, in terms of DFS and OS for carboplatin/paclitaxel compared to cisplatinum/5-FU as dCRT treatment in EC patients. Toxicity rates were lower in the carboplatin/paclitaxel group together with a higher treatment compliance. Carboplatin/paclitaxel as an alternative treatment for cisplatinum/5-FU is a good candidate regimen for further evaluation.