Initial evidence suggests that the WHO Disability Assessment Schedule (WHODAS 2.0) is valid and reliable in general youth populations; however, its psychometric properties in specific subgroups are less established. The primary objective was to test for measurement invariance of the 12-item WHODAS 2.0 in an epidemiological sample of youth aged 15 to 19 years with and without physical or mental conditions. Using data from 1,851 youth in the Canadian Community Health Survey–Mental Health, invariance was tested using multiple-group confirmatory factor analysis. Within-domain item correlations were significant and ordinal coefficient alphas were .91, .94, .93, and .92 for the healthy control, physical, mental, and comorbid groups, respectively. Partial measurement invariance was demonstrated for the WHODAS 2.0, with evidence of noninvariance for item residuals and factor variances related to cognition and participation. While these domain-specific comparisons may be biased, valid comparisons of overall disability across subgroups of youth can be made with confidence.