Background: Prior work has shown that fibrinogen, an accepted pro-inflammatory marker, predicts cardiovascular (CV) events. While it is known that physical activity imparts CV health benefits, its impact on systemic inflammation has not been fully explored. Objectives: To investigate the relationship between activity, inflammation, and CV death, we tested the hypotheses that, (i) activity results in less CV death, and (ii) the CV benefit of activity is partially due to lower systemic inflammation. Methods: We examined the association between activity (leisure-time plus occupational as METS-hours per week) and CV death among 4,038 adults (mean age 56 ± 3) without baseline CV disease in phase I of Strong Heart Study (1989-1991), a longitudinal study among American Indians. Regression models were used to assess associations between activity, fibrinogen and CV death. Kaplan-Meir analysis was used to plot survival based on activity. Results: After 10 years of follow-up (1989-1999), 308 fatal CV events occurred. Compared to subjects with minimal activity, those with higher activity levels had a significantly lower risk of CV death (p=0.002, Fig 1A). Odds ratios were 0.79 (95% CI: 0.59-1.06), 0.65 (0.48-0.88), and 0.46 (0.33-0.65) for increasing activity (in quartiles), after adjustment for age, sex, smoking, diabetes, hypertension, LDL, and renal disease. In addition, increasing activity was associated with lower fibrinogen levels (p<0.001; Fig. 1B). Moreover, increasing activity resulted in lowest CV death in subjects with low fibrinogen levels, a benefit that extended to patients with high fibrinogen levels (Fig 1C). These results persisted independent of traditional CV risk factors and body fat (p<0.001). Conclusion: In a population-based study of American Indians, physical activity was associated with less CV death, in part, mediated via an anti-inflammatory pathway. This study identifies activity as an important modulator of CV outcomes among American Indians, possibly due to lower levels of systemic inflammation.