A higher relative risk of thrombotic cardiovascular complications has recently emerged in studies evaluating the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as rofecoxib, celecoxib, and naproxen. Direct pro-thrombotic effects of selective cyclooxygenase-2 inhibition were originally speculated to be the potential mechanism behind these results, but this proposal fails to explain the pro-thrombotic effects of non-selective NSAIDs. We hypothesize that the paradoxical pro-inflammatory, pro-thrombotic effects associated with chronic use of anti-inflammatory agents are attributable to compensatory host response rather than direct effects of the drugs. Chronic pharmacologic inhibition of inflammation may induce physiologic dependence, and cessation of therapy has been shown to produce rebound effects in aspirin, statins, and other immunomodulatory agents. By down-regulating inflammatory pathways in a pulsatile fashion, chronic use of NSAIDs may promote compensatory up-regulation of these same pathways and shift the host baseline equilibrium towards an inflammatory state. The host may be susceptible to inflammation between intermittent doses and after withdrawal of therapy. Inflammation is a promoter of adrenergia and thrombosis, and the constellation of these effects may predispose to excess risk of acute cardiovascular events.