Introduction: Acute systemic inflammation or infection transiently increases arterial stiffness, while high levels of cardiorespiratory fitness are associated with decreased inflammation and arterial stiffness in older adults. We tested the hypothesis that high cardiorespiratory fitness (CRF) would partially prevent the unfavorable effect of arterial stiffness produced by acute systemic inflammation in older adults. Methods: Using a randomized double blind sham placebo-controlled design, 40 healthy older adults (male 20, female 20; age 67짹5 yrs) were assigned to receive either an influenza vaccine (n=20) as a model to generate systemic inflammation or a sham vaccine (n=20). Subjects were divided into high CRF (34짹6 ml/kg/min) or low CRF (26짹3 ml/kg/min) group by peak oxygen uptake. C-reactive protein and interleukin 6 were measured as markers of inflammation and carotid-femoral pulse wave velocity (PWV), as an index of arterial stiffness, was assessed before and 48 hours after each vaccination. Results: Compared with sham placebo, the influenza vaccination caused a significant increase in C-reactive protein (p=0.015) and interleukin 6 (p=0.043) compared with baseline vaccine. Carotid-femoral PWV was significantly increased after influenza vaccination (9.4짹1.7 to 10.3짹2.1 m/s, p<0.05), but not sham vaccination (9.5짹1.2 to 9.4짹1.3 m/s, NS). Interestingly, the high CRF group had an attenuated increase in carotid-femoral PWV compared to the low CRF group (∆0.40.짹0.13 vs. ∆1.31짹0.39 m/s, p=0.04) after acute inflammation. Conclusions: These findings show that acute inflammation significantly increases arterial stiffness in older adults, but these increases were attenuated in the high CRF group compared to the low CRF group. High cardiorespiratory fitness may have a cardioprotective effect in older adults exposed to acute inflammatory stimuli.