Few data are available to evaluate health-related quality of life (HRQOL) of people with irritable bowel syndrome (IBS). We evaluated and compared the impact of IBS on HRQOL using previously reported HRQOL data for the U.S. general population and for people with selected chronic diseases. Using the SF-36 Health Survey, we compared the HRQOL of IBS patients (n = 877) with previously reported SF-36 data for the general U.S. population and for patients with gastroesophageal reflux disease (GERD), diabetes mellitus, depression, and dialysis-dependent end-stage renal disease (ESRD). On all 8 SF-36 scales, IBS patients had significantly worse HRQOL than the U.S. general population (P < 0. 001). Compared with GERD patients, IBS patients scored significantly lower on all SF-36 scales (P < 0.001) except physical functioning. Similarly, IBS patients had significantly worse HRQOL on selected SF-36 scales than patients with diabetes mellitus and ESRD. IBS patients had significantly better mental health SF-36 scale scores than patients with depression (P < 0.001). IBS patients experience significant impairment in HRQOL. Decrements in HRQOL are most pronounced in energy/fatigue, role limitations caused by physical health problems, bodily pain, and general health perceptions. These data offer further insight into the impact of IBS on patient functional status and well-being.