© 2020 Leavitt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Biomarkers of chronic inflammation (such as C-reactive protein) have long been associated with cardiovascular disease and mortality; however, biomarkers involved in antiviral cytokine induction and adaptive immune system activation remain largely unexamined. We hypothesized the cytokine interferon gamma inducible protein 10 (IP-10) would be associated with clinical and subclinical cardiovascular disease and all-cause mortality in African Americans. We assessed these associations in the Jackson Heart Study (JHS) cohort and the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. There was a modest association of IP-10 with higher odds of left ventricular hypertrophy (OR = 1.20 (95% confidence interval (CI) 1.03, 1.41) per standard deviation (SD) higher natural log-transformed IP-10 in JHS). We did not observe associations with ankle brachial index, intima-media thickness, or arterial calcification. Each SD higher increment of ln-transformed IP-10 concentration was associated with incident heart failure (hazard ratio (HR) 1.26; 95% CI 1.11, 1.42, p = 4x10-4) in JHS, and with overall mortality in both JHS (HR 1.12 per SD, 95% CI 1.03, 1.21, p = 7.5x10-3) and REGARDS (HR 1.31 per SD, 95% CI 1.10, 1.55, p = 2.0 x 10−3), adjusting for cardiovascular risk factors and C-reactive protein. However, we found no association between IP-10 and stroke or coronary heart disease. These results suggest a role of IP-10 in heart failure and mortality risk independent of C-reactive protein. Further research is needed to investigate how the body’s response to chronic viral infection may mediate heart failure and overall mortality risk in African Americans.