Few studies have assessed the role of sociodemographic characteristics on outcomes after a cholecystectomy. Our goal was to evaluate the influence of age and gender on the health related quality of life (HRQoL) changes after cholecystectomy in this prospective observational study of consecutive patients undergoing cholecystectomy. Patients completed the SF-36 and the Gastrointestinal Quality of Life Index (GIQLI) before intervention and 3 months later. The influence of age, gender, and the pre-intervention health status on the HRQoL changes was studied by multivariate regression analysis. Older patients had poorer HRQoL and their post-intervention improvement was lower than younger patients. Compared with men, women had worse health status before the intervention measured with both HRQoL tools. In the unadjusted analysis women had greater improvements than men, measured by the GIQLI, but not with the SF-36. However, after controlling for other relevant variables, the SF-36 measured lower improvements in women more often than men, but the GIQLI showed similar results for both. For men and women, the lower the pre-intervention health status the higher the post-operative improvement. Women presented with worse health status before the intervention and less improvement post-operatively after adjustments. The pre-intervention health status has an important role explaining changes after the intervention. A gender-related difference exists between what a generic and a disease-specific HRQoL instrument captures when measuring HRQoL improvement after cholecystectomy.