Background Previous epidemiological studies have consistently found a positive family history of esophageal cancer is associated with a significantly increased risk of the cancer. However, whether the elevated risk could be attributed to common household exposure or inherited susceptibility is uncertain. This study aimed to highlight the effect of genetic predisposition by noting the significant differences in onset age and multiple primary cancers between esophageal squamous cell carcinoma (ESCC) cases with or without a positive family history of the cancer. Methods Age at onset and the percentage of multiple primary cancers were compared between ESCCs with (n=766) or without (n=1 776) a positive family history of the cancer in a consecutive surgery cohort at the Department of Thoracic Surgery of Hebei Tumor Hospital and the Fourth Hospital of Hebei Medical University. Results Overall, ESCCs with a positive family history of the cancer featured both a significantly younger age of onset and significantly more multiple primary cancers than those with a negative family history (onset age 51.83 vs. 53.49 years old, P<0.01; percent of multiple primary cancers 5.50% vs. 1.70%, chi(2)= 25.42, P<0.01). Both the differences were evident in subgroup analyses, but did not correlate. While age at onset differed significantly by family history among the male, smoking, and drinking groups, the difference of multiple primary cancers was significant among the otherwise nonsmoking, nondrinking, and younger onset age groups. Conclusions Younger age of onset and multiple primary cancers associated with ESCCs with a positive, as opposed to a negative family history of the cancer, suggest a genetic predisposition. The results of subgroup analyses indicate a younger age of ESCC development results from the interaction of environmental and genetic risk factors, but multiple primary cancers may be related only to genetic predisposition.