The purpose of this study was to evaluate the health-related quality of life among patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA), or systemic lupus erythematosus (SLE). This prospective, cross-sectional survey was conducted from September 1, 2008 to August 31, 2009. Patients answered questions with regard to demographics and disease characteristics and also completed generic (SF-36) and preference-based utility (SF-6D and EQ-5D) instruments. Multivariate analysis assessed the relationship of RA and SLE to AS with respect to the outcomes of the different health-related quality of life instruments. In general, baseline and disease characteristics differed across the three disease groups. Compared to SLE patients, RA patients scored worse on the higher-order summary scores of physical (PCS) and mental components (MCS) of SF-36 (P <0.002) and total SF-36 (P <0.005). RA also had worse PCS than AS (P <0.001). SLE patients scored higher on the utility score of SF-6D compared with RA patients and higher than both AS and RA patients for the utility score of EQ-5D. Multivariate analysis found that compared with AS patients, RA had significantly lower SF-36 total score and PCS, and SLE patients had greater PCS and a greater EQ-5D utility score. Multivariate analysis found no difference across the patient groups with respect to MCS or SF-6D utility score. These findings suggest that among the three rheumatic diseases studied, RA patients have the worse health-related quality of life, and AS patients have similar or poorer health-related quality of life as SLE patient.