Background: Quality of life (QOL) is reduced in patients with irritable bowel syndrome (IBS) and little is known about differences in QOL in relation to referral status, gender and predominant bowel pattern in IBS patients. This study aimed to explore these relationships. Methods: 343 patients with IBS according to the Rome I criteria (251 females, 92 males) completed five different self-administered questionnaires to evaluate QOL. There were 119 patients with diarrhea-predominant IBS (IBS-D), 93 with constipation-predominant IBS (IBS-C) and 131 with alternating constipation and diarrhea (IBS-A). The study group comprised 209 hospital outpatients and 134 primary care patients. The questionnaires were mailed to the patients with an overall response rate of 88%. Results: QOL was reduced in hospital outpatients compared to primary care patients, but only in females. IBS subgroup (IBS-D), physical fatigue and general health independently predicted referral to a gastroenterologist. Females had lower QOL than males. No differences, except in severity of diarrhea and constipation, were observed between IBS subgroups. Perceived fatigue was related to well-being, psychological and gastrointestinal symptoms. Independent predictors for fatigue were depression, trait anxiety, general health and vitality, along with eating dysfunction and female sex. Conclusion: IBS female patients seen in referral centers versus primary care is a highly selected group with reduced QOL. QOL in IBS is affected by gender, but not by subgroup. Our findings have implications for the generalizability of results in IBS trials. Fatigue is a common symptom in IBS that correlates to general well-being and psychological and subjective gastrointestinal symptoms.