Health-related quality of life (HRQoL) research suggests that, due to unique characteristics of a disease state, disease specific tools are better discriminators of health status than generic tools. OBJECTIVE: To compare generic (SF-12) versus disease specific (SIBDQ) quality of life tools in a cohort of patients receiving treatment for Crohn’s Disease (CD). METHODS: Structural Equation Modeling techniques were used to evaluate the effectiveness of the SF-12 and the SIBDQ for evaluating health status patients with CD. A cohort of 151 patients with CD receiving drug therapy was administered both instruments via telephone survey. RESULTS: The variance explained by the SIBDQ in this population was 11.6% while the SF-12 explained 55.7%. Adapted models of both the SIBDQ and SF-12 resulted in explained variance of 54.8% and 84.1%, respectively. CONCLUSIONS: Given these results, the generic HRQoL tool was significantly better than the disease specific tool at measuring and accounting for health status in this population. Patients with moderate or severe CD have previously been shown to have differing clinical response to therapy based upon disease severity, whereby patients with more severe disease have better response. Due to these possible unique clinical outcomes of newer medications such as infliximab, the effectiveness of disease specific tools may be compromised since improving therapies may affect HRQoL in a different manner than therapies previously available. Other innovative therapies, such as biologic response modifiers for rheumatoid arthritis, may have similar findings related to HRQoL measurement. This potential problem with HRQoL measurement is likely to increase as biopharmaceutical and pharmacogenomic research increases the number and rate of new product approvals. These findings have important implications related to measurement of HRQoL in clinical trials and pharmacoeconomic evaluation of medications. This suggests a need for careful reevaluation of disease specific tools given the clinical effects of newer therapies.