A simple diagnostic model based on the quantification of complement-derived fragment C4c and cancer antigens, i.e., 21.1 (CYFRA 21-1) and C-reactive protein (CRP), was able to discriminate between benign and malignant pulmonary nodules (AUC, 0.86), with a high specificity (92%) in a cohort of individuals enrolled in a CT-screening program. The gene discussed is CRP; the disease is cancer.