In recent years, there has been a growing interest in the assessment of quality of life (QOL) issues, particularly in chronic debilitating conditions. Several instruments have been developed, tested, and validated in the general population and in other chronic diseases; however, few studies have examined QOL issues in adults with sickle cell disease (SCD). We developed Sickle Cell Impact Measurement Scale (SIMS), an instrument for measuring the QOL of adults with SCD. The 142-item multi-dimensional SIMS questionnaire was developed using 4 validated instruments and additional questions based upon recommendations of patient focus groups. The SIMS was self-administered to 106 SCD and 45 rheumatoid arthritis (RA) patients over 4 sites. SIMS was evaluated on measures of both internal consistency and construct validity. Item reduction was performed based on results of factor analysis. The SIMS achieved good internal consistency, with a Cronbach's alpha coefficient reported of 0.86, and distinguished between patients with SCD and RA. Overall, QOL did not differ significantly among SCD and RA patients. However, SCD patients scored higher in both physical and social domains, which was expected and reflected the differences in the pathophysiology of each disease. The SIMS is a reliable, valid, and responsive questionnaire, which functions well as a discriminative instrument for the measure of health-related QOL (HRQOL) of adults with SCD. The SIMS is currently being administered to adults with SCD across several centers for further validation to become a disease-specific, global QOL instrument. Am. J. Hematol., 2008. © 2007 Wiley-Liss, Inc.