The Irritable Bowel Syndrome (IBS)-Quality of Life (QOL) is the most extensively validated health-related quality of life (HRQOL)-specific instrument for IBS with appropriate evidence for psychometric validity. Our aim was to linguistically validate the IBS-QOL for Mexico according to standard guidelines, to conduct further psychometric validation, and to compare the HRQOL between IBS patients from Mexico and North Carolina (University of North Carolina). Construct validity was tested by correlating scores from the Mexican Spanish IBS-QOL with those for anxiety and depression obtained by the Hospital Anxiety and Depression scale. Also, HRQOL from Rome I female IBS patients who consulted a tertiary referral center in Mexico was compared with that of female patients from UNC matched by age and bowel habit. A general univariate linear model was done to determine the most important variable over HRQOL, place of origin, or bowel habit. The majority of the IBS-QOL items had a negative correlation with depression as well as with anxiety. Compared to patients from UNC, the Mexican ones reported significant lower scores on Body Image and Health Worry and a trend in Interference with activities and in the Overall score. There were some differences in Dysphoria and Interference that were related to bowel habit, independently of the place of origin. In conclusion, the IBS-QOL validated in Mexican Spanish has shown construct validity. Using this instrumentwe found that female IBS patients who consulted a tertiary referral center in Mexico have lower HRQOL than those in North Carolina at least in factors such as Body Image and Health Worry.