Abstract Background Criticisms that generic measures of health-related quality of life (HRQoL) are not sensitive to impairment in anorexia nervosa (AN) has spurred the development of disease-specific measures. This study aimed to compare the psychometric properties of a generic to a disease-specific measure of HRQoL. Methods 63 participants with AN completed measures of a generic HRQoL (SF-12), disease-specific HRQoL (Eating Disorders Quality of Life Questionnaire; EDQOL), functional impairment (days out of role; DOR; Work and Social Adjustment Scale; WSAS), and eating disorder severity (Eating Disorder Examination; EDE) at baseline, post-treatment, and 6- and 12-months follow-up. Cronbach’s α was computed for the SF-12 and EDQOL (internal consistency). Correlations were assessed between SF-12/EDQOL scores and DOR, WSAS, and EDE scores (convergence validity). Three sets of three multiple linear regressions were performed using SF-12 and EDQOL scores as predictors and change in DOR, WSAS, and EDE global scores from baseline to (i) post-treatment, (ii) 6-month follow-up, (iii) and 12-month follow-up as dependent variables (predictive validity and sensitivity). Results The EDQOL displayed stronger internal consistency (α = 0.92) than the SF-12 (α = 0.80). The SF-12 converged more strongly with DOR and the WSAS ( r p = −0.31 to −0.63 vs. 0.06 to 0.70), while the EDQOL converged more strongly with the EDE ( r p = −0.01 to 0.48 vs. -0.01 to −0.37). The SF-12 demonstrated stronger predictive validity (β = −0.55 to 0.29) and sensitivity to changes in ED severity (β = −0.47 to 0.32). Conclusions The SF-12 is a valid and sensitive measure of HRQoL impairment in patients with AN. While the SF-12 may be preferred in research comparing EDs to other populations, and in research and practice as an indicator of functional impairment; the EDQOL may be preferred by clinicians and researchers interested in HRQoL impairment specifically associated with an ED and as an additional indicator of ED severity.