OBJECTIVES: Diseases are often described and studied as if they occur in isolation, yet there is increasing recognition of the complex interrelatedness of diseases and treatment outcomes in patients with multiple chronic diseases. The objective of this study was to describe the incremental impact of diseases involving chronic inflammation (chronic obstructive pulmonary disease (COPD), osteoarthritis (OA) and rheumatoid arthritis (RA)) on survival when co-occurring with different combinations of other chronic diseases. METHODS: A cohort aged 55-64 years from the national database of Veteran's Affairs was identified with one or more of the following conditions: COPD, diabetes, hypertension, RA, OA, asthma, depression, ischemic heart disease, dementia, stroke, and cancer. Clusters of mutually exclusive disease combinations were created and five-year all-cause mortality rates were calculated. The relative risk of mortality associated with additive effect of presence of COPD, OA, and RA in common disease clusters was estimated. RESULTS: A total of 741,847 persons were identified (mean age = 59.2 yrs [SD = 3.1]). Five-year mortality rates were lowest among persons with a single condition and followed a logical progression of higher mortality rates with more chronic conditions. A major exception was presence of OA as a co-morbid condition. OA was associated with a significantly lower risk of 5-year mortality compared to the chronic condition(s) alone: COPD (RR=0.73 [95% CI, 0.65, 0.81]); ischemic heart disease (0.63 [0.52, 0.76]); hypertension (0.77 [0.71, 0.83]); dementia (0.63 [0.42, 0.93]); depression (0.65 [0.50, 0.84]); hypertension plus diabetes (0.85 [0.77, 0.93]); and ischemic heart disease plus hypertension (0.83 [0.73, 0.94]). CONCLUSIONS: The association of OA with reduced rates of five-year mortality with other chronic diseases is a compelling result. Replicating these findings in other large population-based databases is an important next step in order to begin exploring possible causative relationships.