Background: Lung cancer may cause severe impairment of quality of life. An increasing number of lung cancer patients are receiving outpatient chemotherapy. However, little is known about gender aspects in the areas of impaired QoL in outpatient versus inpatient lung cancer patients. The aim of the study was to investigate this. Methods: We report from a prospective, multicenter study to analyze the EORTC QLQ-LC29, a new designed module to assess the QoL of lung cancer patients. The participants filled out the EORTC QLQ-C30 and the recently updated lung cancer module QLQ-LC29.Results: A total of 198 lung cancer patients (73 female and 125 male, mean 64.5 age years) during first-line therapy were enrolled in this study by completing the both questionnaires. Women showed higher symptom scores, when being inpatient. Significant results were found regarding nausea/vomiting (mean women = 17.6 and mean men = 9.3, p = 0.037) and hair loss (mean women = 40.0 and mean men = 21.7, p = 0.010), although women received fewer chemotherapy treatments than their male counterparts (women n = 47, 64.4% and men n = 86, 68.8%). When it comes to global QoL, men report a significant worse QoL than women (mean women = 57.5 and mean men = 46.1, p = 0.016), when being inpatient. As outpatients, men report significant results regarding sore mouth and tongue (mean women = 1.2 and mean men = 13.5, p = 0.012). Conclusion: This study adds to the literature in showing the typical gender difference effect on QoL, suggesting men suffer less than women, is not a universal phenomenon irrespective of being inpatient or outpatient. It also confirms the hypothesis that the symptom burden is higher with inpatients than outpatients.