Cancer of the esophagus has a poor long-term prognosis and a high peri-operative morbidity in which pulmonary complications play a major role. The combination of the surgical approach, pre-existing pulmonary disorders, poor nutritional status and the release of pro-inflammatory cytokines may be contributing factors. N-acetylcysteine ((NAC) has been shown to have oxygen scavenging abilities. In severe sepsis and acute respiratory distress syndrome, positive effects of NAC on morbidity and mortality were discovered. In this observational study peri-operative high dose NAC was administered in 22 patients. The effects of this treatment on respiratory function, morbidity and survival were studied. These prospectively collected data were compared with data of a matched, retrospective group without NAC treatment. There were no significant differences between the groups in terms of socio-demographic data, preoperative pulmonary function, intra-operative course and oncologic characteristics. The oxygenation indices at the postoperative hours 2 (P = 0.019), 4 (P < 0.001), 8 (P = 0.035), 12 (P = 0.035) and 24 (P = 0.046) were significantly higher in the NAC group. After 36 h, the difference between groups was no longer significant (P = 0.064). NAC-treated patients showed significant lower overall pulmonary morbidity, 45.5% versus 81.8% (P = 0.027). Surgical morbidity, intensive care unit and hospital stay were not significantly different between groups, mortality was zero. Kaplan-Meier curves showed no significant difference in survival 12 months postoperatively. These data indicate that postoperative oxygenation can be improved and rate of overall pulmonary complications is reduced using peri-operative high dose NAC in transthoracic esophagectomy.