Little is known about the etiology of esophageal and gastric cardia adenocarcinoma (EGA), a cancer with one of the fastest-rising incidences in the developed world. To explore the etiology of this cancer, we conducted a retrospective cohort analysis using data from the Surveillance, Epidemiology and End Results Program of the United States National Cancer Institute to study EGA and esophageal squamous cell carcinoma (ESC), in association with cancers of other sites. Standardized incidence ratios, adjusted for age, sex, and time period, were calculated as a measure of the relative risk (RR) of developing a second primary cancer (EGA or ESC) following a given first primary site. We found a moderately elevated risk of EGA following cancers of the lung (RR = 1.9 in men and RR = 2.0 in women) and of the head and neck (RR = 2.1 in men and RR = 6.3 in women) and a strongly elevated risk of ESC following cancers of the lung (RR = 2.8 in men and RR = 5.1 in women) and of the head and neck (RR = 9.6 in men and RR = 38.8 in women). A significantly elevated risk following breast cancer in women was observed for both EGA (RR = 2.6; 95% confidence interval, 1.8-3.7) and ESC (RR = 1.4; 95% confidence interval, 1.1-1.9). We also found a significantly elevated risk of EGA following bladder (RR = 2.0), colorectal (RR = 1.7), and prostate (RR = 1.4) cancer in men and of ESC following colorectal cancer (RR = 1.7) in women in this study. The strong association with tobacco-related malignancies in this study reinforces the role of tobacco in the etiology of esophageal cancers, which appears stronger for squamous cell carcinoma than for adenocarcinoma and stronger in women than in men. The study also suggests a possible shared etiology between esophageal adenocarcinoma and colorectal cancer in men and provides new evidence about the association of both adenocarcinoma and squamous cell carcinoma of the esophagus with breast cancer in women. Findings of this study provide clues to the etiology of EGA and ESC.