Debate continues on how to measure and weight diseases in multimorbidity. We quantified the association of a broad range of chronic diseases with physical health–related qualify of life and used these weights to develop and validate a multimorbidity weighted index (MWI). Community-dwelling adults in 3 national, prospective studies—the Nurses' Health Study (n = 121,701), Nurses' Health Study II (n = 116,686), and Health Professionals Follow-up Study (n = 51,529)—reported physician-diagnosed diseases and completed the Short Form 36 physical functioning (PF) scale over multiple survey cycles between 1992 and 2008. Mixed models were used to obtain regression coefficients for the impact of 98 morbid conditions on PF. The MWI was formed by weighting conditions by these coefficients and was validated through bootstrapping. The final sample included 612,592 observations from 216,890 participants (PF mean score = 46.5 (standard deviation, 11)). The association between diseases and PF varied severalfold (median, −1.4; range, −10.6 to 0.8). End-stage organ diseases were associated with the greatest reduction in PF. The mean MWI score was 4.8 (median, 3.7; range, 0–53), and the mean number of comorbid conditions was 3.3 (median, 2.8; range, 0–34). This validated MWI weights diseases by severity using PF, a patient-centered outcome. These results suggest that simple disease count is unlikely to capture the full impact of multimorbidity on health-related quality of life, and that the MWI is feasible and readily implemented.