While measures of health-related quality of life (HRQOL) are increasingly being used as outcomes in clinical trials, it is unknown whether HRQOL assessments are influenced by the method of administration. We compared telephone, face-to-face, and self-administration of a commonly-used HRQOL measure, the SF-36. Veterans (N = 172) receiving care in the General Medicine Clinic were randomized into groups differing only in order of administration. All patients were asked to complete the SF-36 three times over a 4-week period. The SF-36 demonstrated high internal consistency, regardless of mode of administration, but showed large variation over short intervals. This variation may: (1) increase dramatically sample size requirements to detect between-group differences in randomized trials and (2) reduce the SF-36's usefulness for clinicians wishing to follow individual patients over time.