Rheumatoid arthritis (RA) affects approximately 0.5-1% of the population and imposes substantial societal costs including an increased risk of work-related disability and accelerated mortality. It is increasingly clear that RA-related co-morbidities, including cardiovascular disease (CVD), infection, osteoporosis, lymphoproliferative malignancy, and peptic ulcer disease, serve as major determinants of disease-associated outcome. In this review, the impact of these select co-morbidities on RA outcome is discussed. In addition, this review explores potential mechanisms underlying their association with RA, the possible iatrogenic role of agents used to treat the disease, and measures aimed at both prevention and treatment of disease-specific co-morbidity.