Using a disease specific instrument to measure the health related quality of life (HRQOL) of patients with inflammatory bowel disease (IBD), it has been shown that their perceived HRQOL worsens during active disease. The precise factors involved in HRQOL changes reported by these patients are largely unknown. Our aim was to elucidate which socio-demographic and health status variables are related with HRQOL in IBD patients. To this end, 354 patients with IBD were interviewed. To quantify the impairment in the HRQOL, the 36-item version of the inflammatory bowel disease questionnaire (IBDQ) was administered to all patients. To explore the relation of each individual variable on the HRQOL an univariate analysis by using the Spearman correlation, the Mann-Whitney or the Kruskal-Wallis test was performed when necessary. Factors significant at the univariate analysis were assessed using multiple linear regression modeling with global IBDQ score as the dependent factor. Results: Disease type did not predict IBDQ score in the univariate nor in the multivariate analysis. Consequently, statistical analysis was performed in the globai group of 354 patients independently of the type of disease. Lower recurrence/year index, longer disease duration, higher level of education, symptom activity, male gender and non-necessity of hospitalization all predict a better HRQOL (p < 0.05). Factors which remained significant (p < 0.05) in the multiple regression modeling were gender, need of hospitalization, symptomatic activity, recurrence/year index and education level. Conclusions: Symptomatic activity and socio-demographic variables such as gender and education are the most important factors involved in the impairment of HRQOL in patients with IBD.