Knowledge of how factors related to esophageal cancer resection affect long-term quality of life after surgery is scarce, and no population-based studies are available. Therefore, we conducted a Swedish nationwide, prospective, population-based study of how esophageal surgery-related factors influence quality of life 6 months postoperatively. The Swedish Esophageal and Cardia Cancer register (SECC-register) encompasses 174 hospital departments (97%). Microscopically radically operated patients responded to a validated written questionnaire assessing quality of life. The basic questionnaire (QLQ-C30) and the esophagus-specific module (OES-24) were developed by the European Organization for Research and Treatment of Cancer. The Mann-Whitney test, the Jonckheere-Terpstras test, and logistic regression were used in statistical analyses. Among 100 included patients, the occurrence of surgery-related complications was the main predictor of reduced global quality of life 6 months after surgery (p for trend = 0.03). This effect remained after adjustment for potential confounding variables. Except for anastomotic strictures, each of the predefined complications--i.e., anastomotic leakage, infections, cardiopulmonary complications, and operative technical complications--contributed to decreased quality-of-life scores. Other potentially relevant factors--e.g. degree of lymph node dissection, resection margins, operative blood loss or duration, and hospital type--did not significantly affect quality of life. In conclusion, any measures that can reduce the risk of major surgery-related complications can decrease the negative impact on quality of life after esophageal cancer surgery. More population-based studies are warranted, however.