This study divided patients with esophageal cancer and multiple primary cancers into two groups, a head and neck cancer (HNC) group and a non-head and neck cancer (NHNC) group. These groups were then evaluated on the basis of clinical and pathological studies. Among 92 patients with esophageal cancer as one of multiple primary cancers, 38 (41.8%) were assigned to the HNC group. The following characteristics distinguished patients in the HNC group from those in the NHNC group: (1) younger age; (2) shorter interval between diagnosis of metachronous cancers; (3) many displayed superficial esophageal cancer. Among the cases in which esophageal cancer was discovered synchronously with head and neck cancer, head and neck cancers were discovered before esophageal cancer; and (4) many patients displayed esophageal dysplasia, and many had multiple esophageal cancers. In the present study, we demonstrated the necessity of screening for multiple primary cancers in patients with esophageal cancer.