Objective With the International Classification of Functioning, Disability and Health (ICF), the impact of health conditions on functioning and disability can be described. A Comprehensive and a Brief ICF Core Set for osteoarthritis (OA) were developed. Our specific aims were to validate the Brief ICF Core Set for OA using a novel approach, i.e., to identify ICF categories that best explain patients' functioning, and to propose a statistically validated version. Methods We performed a psychometric study using group lasso regression on data from a convenience sample of 879 OA patients from 20 countries. The general health subscale of the Medical Outcomes Study Short Form 36 was used as a dependent variable, and all ICF categories of the Comprehensive ICF Core Set for OA and some sociodemographic and disease-specific characteristics were used as independent variables. The most relevant ICF categories were identified as those showing a significant effect based on the pointwise 90% confidence intervals resulting from 1,000 bootstrap trials. Results The set of ICF categories that best explains patients' functioning consists of 4 body functions, 2 body structures, 2 activities and participation, and 3 environmental factors. Twelve of the original 13 Brief ICF Core Set categories were confirmed, and 3 additional ICF categories were identified. Conclusion Our findings reassure the validity of the Brief ICF Core Set for OA. The statistically validated Core Set with the additional statistically derived ICF categories will likely perform better with regard to discrimination and sensitivity to change in studies and trials, and should be further explored in the future.