Introduction: Studies comparing the performance of health-related quality of life instruments in osteoporosis are lacking. We compared the feasibility, validity and reliability of the osteoporosis quality of life questionnaire (OQLQ) and the QUALEFFO (test version) in women with vertebral deformities due to osteoporosis. Methods: Three hundred and thirty-eight patients diagnosed with primary osteoporosis and vertebral deformity and a random sample of 304 women from the general population (control group) were recruited. Patients and controls were randomly assigned to receive either the OQLQ or the QUALEFFO, and the SF-36 and EQ-5D. Test–retest reliability was assessed in the patient group. Results: The QUALEFFO had more items with missing data and took slightly longer to administer (20.7 vs. 18.7 min). Cronbach's α and intraclass correlation coefficient (ICC) values for OQLQ domains (α: 0.75–0.91; ICC: 0.85–0.93) were slightly higher than for the QUALEFFO (α: 0.63–0.90; and ICC: 0.80–0.93). OQLQ and QUALEFFO domain scores correlated as expected with SF-36 and EQ-5D domains. Both questionnaires discriminated between patients and controls though the OQLQ showed slightly better discriminant power. Discussion: The superior performance of the OQLQ in terms of administration time, missing responses, and discriminatory capacity needs to be weighed against the advantages of using a self-administered instrument such as the QUALEFFO. A full comparison also requires data on sensitivity to change.