It is unclear whether cannabis use in humans plays a role in the regulation of inflammatory responses. This study aimed to examine cannabis-attributable immunomodulation as manifested in levels of fibrinogen, C-reactive protein (CRP), and interleukin-6 (IL-6). The Coronary Artery Risk Development in Young Adults (CARDIA) study is a cohort of 5115 African-American and Caucasian males and females enrolled in 1985-1986, and followed up for over 25 years, with repeated measures of cannabis use. Fibrinogen levels were measured at year 5, year 7, and year 20, CRP levels were measured at year 7, year 15, year 20, and year 25, and IL-6 levels were measured at year 20. We estimated the association of cannabis use and each biomarker using generalized estimating equations adjusting for demographic factors, tobacco cigarette smoking, alcohol drinking, and body mass index. Compared with never use (reference), recent cannabis use was not associated with any of the biomarkers studied here after adjusting for potential confounding variables. Former cannabis use was inversely associated with fibrinogen levels (β = -5.4; 95% confidence interval [CI], -9.9, -0.9), whereas the associations were weaker for serum CRP (β = -0.02; 95% CI, -0.10, 0.06) and IL-6 (β = -0.06; 95% CI, -0.13, 0.02). A modest inverse association between former cannabis use and fibrinogen was observed. Additional studies are needed to investigate the immunomodulatory effects of cannabis while considering different cannabis preparation and mode of use.