Previously, we observed a strong relationship between circulating serum inflammation proteins in relation to lung cancer diagnosis and risk, both in case-control and prospective cohorts. Low-dose computed tomography (LDCT) screening has a high prevalence of false-positive nodules, thus companion noninvasive biomarkers that can distinguish between benign and malignant nodules could have clinical utility and positive impact on patient outcomes. We conducted a nested case-control study within the National Lung Screening Trial. Concentrations of 30 inflammation proteins were measured on plasma samples of 262 cases and 528 controls using a highly sensitive and analytically validated electrochemiluminescence V-PLEX immunoassay. Comparing the fourth quartile with the first quartile, we found increased IFNγ and IL12/IL23p40 associated with increased odds of a lung cancer diagnosis OR 1.89, 95% confidence intervals (CI), 1.16-3.09; OR 2.49, 95% CI, 1.46-4.23, respectively. Confirming our previous observations, we also detected a relationship between increased IL6, IL8, and C-reactive protein (CRP) with lung cancer diagnosis. These relationships were significant after adjustment for age, gender, race, smoking, body mass index (BMI), family history of lung cancer, and previous diagnoses of inflammatory conditions. However, none of these proteins could distinguish between a benign and malignant lung nodule (IL6: OR 1.25, 95% CI, 0.59-2.64; IL8: OR 1.40, 95% CI, 0.70-2.81; CRP: OR 0.98, 95% CI, 0.45-2.12). We have discovered new associations for IFNγ and IL12/IL23p40 with lung cancer but have no evidence that these proteins can distinguish between benign and malignant lung nodules. Circulating inflammation proteins are unlikely to have utility as companion LDCT biomarkers.