In daily clinical practice, the esophageal squamous cell cancer (ESCC) is considered to be more (18)F-FDG avid than adenocarcinoma (EAD). To date, the few studies concerning the existence of a real metabolic difference based on esophageal cancer (EC) histology, show divergent and not definitive results. A retrospective analysis of (18)F-FDG PET/CT of 87 patients with ESCC and EAD was performed to investigate the role played by both histopathological subtype and tumor differentiation in the characterization of glucose metabolic profile of EC. Esophageal squamous cell cancer was well differentiated (WD) in 42 cases and poorly differentiated (PD) in 12 patients. Twenty-one of the 33 patients had WD EAD, while 12 had a PD EAD. The (18)F-FDG maximal standardized uptake value (SUV(max)) was determined for all lesions and used for inter and intra-group comparison. In ESCC, the SUV(max) ranged from 4 to 31 with a mean value of 16±6. In EAD, the SUV(max) ranged from 2 to 25 with a mean value of 10±6. A statistically significant difference (P<0.0001) was found between ESCC and EAD. According to histological classification and tumor differentiation, we obtained the following results: a) the SUV(max) values of WD ESCC and WD EAD were 17±5 (range: 7-31) and 7±3 (range: 2-12) respectively (P<0.00001), b) the SUV(max) values of PD ESCC and PD EAD were 11±4 (range: 4-19) and 17±6 (range: 7-25) respectively (P<0.05). Moreover, a statistically significant difference of SUV(max) values was found between WD and PD ESCC (P<0.005) as well as between WD and PD differentiated EAD (P<0.0001). In order to predict tumor histology (ESCC, EAD) from both SUV(max) and lesion location, a multivariate discriminant analysis was performed on the whole population with a resulting diagnostic accuracy equal to 82% (P<0.00001). In conclusion, we provide additional arguments about (18)F-FDG uptake difference between ESCC and EAD as well as between poorly and well-differentiated forms of both EC histological subtypes.