Background & aims: Gastroesophageal reflux is common among preterm infants and those who are small for gestational age, and it is a strong risk factor for adenocarcinoma of the esophagus. Methods: In a cohort of 3364 individuals born preterm and/or small for gestational age between 1925 and 1949, we assessed the long-term risk for esophageal cancer. Results: The standardized incidence rate ratio for esophageal adenocarcinoma was increased more than 7-fold in the cohort (standardized incidence rate ratio, 7.27; 95% confidence interval, 1.98-18.62), and a birth weight <2000 g was associated with a more than 11-fold increase in risk (standardized incidence rate ratio, 11.5; 95% confidence interval, 1.39-41.5). Conclusions: The associations may be spurious, but if not, they may be explained by increased gastroesophageal reflux during infancy among infants born preterm and/or small for gestational age.