Background: Health-related quality of life (HRQoL) has now become an indispensable outcome measure in many randomized clinical trials and other studies. It provides the patient’s voice in measuring health improvement or decline and assessing treatment effectiveness. A validated Amharic version of HRQoL assessment tool was needed for leprosy clinical trials in Ethiopia. The SF-36 was chosen but a validated Amharic version was not available. We describe how this was developed. Methods: The SF-36 was translated from English into Amharic and evaluated for content acceptability in a patient focus group. Back translation was performed. Validity and reliability of the Amharic SF-36 in leprosy affected individuals was tested with 100 patients with leprosy attending the leprosy clinic at ALERT hospital and compared to the Amharic version of the WHOQOL-BREF. Results: Amharic versions of both the WHOQOL-BREF and the SF-36 had good reliability and validity amongst leprosy affected individuals. Internal consistency reliability estimates for each domain/scale exceeded 0.70. The Amharic SF-36 had better convergent and discriminant validity than WHOQOL-BREF in this group of patients. Good known-group validity was seen in both WHOQOL-BREF and SF-36 in leprosy affected patients. The Amharic SF-36 had good inter-rater reliability with seven out of 8 domains scoring above 0.8 in intra-class correlation. Conclusion: This Amharic version of the SF-36 is a valid instrument to measure HRQoL in studies and clinical settings involving leprosy affected individuals in Ethiopia.