BACKGROUND: Previous studies in patients with primary adrenal insufficiency (PAI) on conventional replacement therapy suggest decreased health-related quality of life (HRQoL), and that patients report more frequently fatigue, increased anxiety and inability to work compared to background population.  OBJECTIVES: To study self-reported health status with EQ-5D in patients with PAI. Patients treated with Plenadren (modified-release hydrocortisone) were compared with patients treated with immediate release hydrocortisone (IRHC) replacement therapy. METHODS: This was a cross-sectional, multi-centre, non-interventional survey of patients with PAI receiving Plenadren or immediate release hydrocortisone (IRHC) replacement.  SUBJECTS: One hundred thirty-four adult patients with PAI of whom 36 (19 females [53%]) were treated with Plenadren and 98 (77 females [79%]) were treated with IRHC, were included. MAIN OUTCOME MEASURE: HRQoL described by the EQ-5D, a generic preference-based measure of health. RESULTS: Patients on Plenadren and on IRHC had a mean ± SD age of 53.1 ± 12.7 years and 48.0 ± 13.1 years, respectively (P=0.043). The majority of the patients were diagnosed more than 5 years ago (69%). The mean ± SD daily Plenadren and IRHC doses were 27.0 ± 6.8 mg and 26.6 ± 10.9 mg, respectively (P=0.807). 47% of the Plenadren patients had been receiving Plenadren and 82% of the IRHC patients had been receiving IRHC for more than 3 years. Patients receiving Plenadren had better HRQoL measured by the EQ-5D questionnaire compared to patients replaced with IRHC (0.81 ± 0.16 vs 0.73 ± 0.24, respectively [P=0.030]). CONCLUSIONS: Replacement therapy with Plenadren in patients with PAI confers measurable benefit on HRQoL relative to IRHC as estimated by the EQ-5D questionnaire, and may therefore be advantageous when compared to IRHC substitution.