Background: The Mediterranean diet has positively influenced various medical conditions, but only a paucity of studies has considered the relation between the Mediterranean diet and quality of life (QOL) among people living in North America. Objective: We investigated whether a higher adherence to the Mediterranean diet (aMED) was associated with better QOL and decreased pain, stiffness, disability, and depression in a large cohort of North Americans from the Osteoarthritis Initiative. Results: Of the 4470 participants (2605 women; mean age: 61.3 y), those with a higher aMED had significantly more favorable scores on all outcomes investigated (P , 0.0001 for all comparisons). After adjustment for potential confounders in linear regression analyses, a higher aMED was significantly associated with a higher SF-12 physical composite scale value (b: 0.10; 95% CI: 0.05, 0.15; P , 0.0001), lower WOMAC scores (except for stiffness), and lower 95% CI: 20.09, 20.01; P = 0.01). An adjusted logistic regression analysis, taking as reference those in the 2 highest quintiles of the aMED score, confirmed these findings. Conclusion: Higher aMED is associated with better QOL and decreased pain, disability, and depressive symptoms. This trial was registered at clinicaltrials.gov as NCT00080171.Am J Clin Nutr 2016;104:1403-9.