The potential role of adiponectin, leptin, IGF-1, and tumor necrosis factor alpha (TNF-α) as biomarkers in colorectal adenoma is not clear. Therefore, we aimed to investigate the blood serum levels of these biomarkers in colorectal adenoma. The case-control study consisted of serum from 180 African American patients with colon adenoma (cases) and 198 healthy African Americans (controls) at Howard University Hospital. We used ELISA for adiponectin, leptin, IGF-1, and TNF-α detection and quantification. Statistical analysis was performed by -test and multivariate logistic regression. The respective differences in median leptin, adiponectin, IGF-1, and TNF-α levels between control and case groups (13.9 vs. 16.4), (11.3 vs. 46.0), (4.5 vs. 12.9), and (71.4 vs. 130.8) were statistically significant ( < 0.05). In a multivariate model, the odds ratio for adiponectin, TNF-α, and IGF-1 were 2.0 (95% CI = 1.6-2.5;  < 0.001), 1.5 (95% CI = 1.5(1.1-2.0);  = 0.004), and 1.6 (95% CI = 1.3-2.0;  < 0.001), respectively. There was a positive correlation between serum adiponectin and IGF-1 concentrations with age ( = 0.17,  < 0.001 and  = 0.13,  = 0.009), TNF-α, IGF-1, and leptin concentration with body mass index (BMI) ( = 0.44,  < 0.001;  = 0.11,  = 0.03; and  = 0.48,  < 0.001), respectively. Also, there was a negative correlation between adiponectin and leptin concentrations with BMI ( = -0.40,  < 0.001), respectively. These data support the hypothesis that adiponectin, IGF-1, and TNF-α high levels correlate with higher risk of colon adenoma and can thus be used for colorectal adenomas risk assessment.