Background: In this study we aim to assess the short term effects of clinically significant Blood Pressure (BP) reduction after a behavioral intervention on systemic inflammation, measured by elevated high sensitivity c-reactive protein (HSCRP), in a high cardiovascular disease (CVD) risk cohort. Methods: The study was conducted among 180 employees of Baptist Health South Florida who had 2 or more CVD risk factors such as obesity, diabetes, hypertension or elevated total cholesterol and was involved in a three-month workplace lifestyle intervention. The intervention focused on nutritional and physical activity modifications. At baseline and at 3 months follow-up, anthropometric, clinical, and laboratory measures were obtained. Significant BP reduction was defined as systolic blood pressure (SBP) reduction ≥ 10mmHg or diastolic blood pressure (DBP) reduction ≥ 5mmHg at 3 months of follow-up. A HSCRP >3mg/L was considered elevated. Results: Over the 3-month study period the median SBP decline was 16mmHg (IQR 4 -23mmHg) while the median reduction in DBP was 10mmHg (IQR 6 -16mmHg). 87% (156 participants) experienced significant BP reduction. Among those without significant BP reduction, the prevalence of elevated HSCRP at baseline was 58% and at follow-up it was 75% (p = 0.125). However, among those who had significant BP reduction, there was significant reduction in the prevalence of elevated HSCRP from 66.7% to 57.1% (p<0.001). In unadjusted conditional logistic regression analyses significant BP reduction was associated with 94% reduction in the risk of elevated HSCRP at follow-up. In a fully adjusted model, this association persisted. Conclusion: Clinically significant reduction in blood pressure over a short period in a high cardiovascular disease risk working population is independently associated with markedly diminished risk of elevate hs-CRP. Longer follow-up intervention studies are required to further understand if these effects are sustained.