Although osteoporosis affects millions of elderly women, the quality of their lives is extremely complex and is only recently being appreciated. We recently used a disease-specific Osteoporosis Quality of Life questionnaire (OQLQ) to measure quality of life for 105 elderly osteoporotic women, and reported that by path analysis, spinal fractures, health perception, and several sociodemographic factors accounted for 63% of the variance in quality of life. On the other hand, bone density, Colles fracture, hip fractures, pharmacologic agents, exercise, and several sociodemographic variables were not significant factors. Of particular note was the positive, indirect effect (via health perception and spinal fractures) that participation in a clinical trial (17.5% of the patients) had on life quality. In order to determine how involvement in a research study might affect health perception in this same cohort we examined OQLQ scores in the five domains of the OQLQ for the 18 post-menopausal osteoporotic women enrolled in two different phase III clinical trials with oral bisphosphonates and 87 osteoporotic women treated conventionally (estrogen, bisphosphonate, calcitonin, calcium/vitamin D) in our metabolic bone clinic. Research and clinical patients did not differ in age, femoral BMD, or number of spinal fractures. However, women in research trials had significantly greater aggregate OQLQ scores (5.67 versus 4.23, P < 0.0001) and perceived health (7.28 versus 5.85, P = 0.001) than clinical patients. These differences were highly significant (P < 0.001) for domains of quality of life including physical function, activities of daily living, symptoms, and leisure/ social activity and marginally significant for the emotional function domain (P = 0.05). Hence, by regression-based path analysis and subgroup analysis of cross-sectional data, participation in a clinical trial had a significant and positive impact on health-related quality of life. If these findings are confirmed by other studies, identifying those factors inherent in clinical studies that positively impact the lives of osteoporotic patients should become as important a priority as development of new therapies for this chronic disease.