BACKGROUND Elevated plasma homocysteine (Hcy) levels are associated with increased risk of colorectal cancer (CRC), particularly in patients with systemic inflammation or chronic conditions. AIM To evaluate serum Hcy levels as a predictive marker of lesion risk and CRC to prioritize patients undergoing diagnostic colonoscopy. METHODS We conducted a prospective cohort study of 301 fecal occult blood test-positive patients at San Agustín University Hospital in Asturias, Spain. Plasma Hcy levels were measured prior to the colonoscopy and classified into three thresholds: ≤ 12, 12-15, and > 15 μmol/L. Colonoscopy and histopathology determined the presence of low-risk, high-risk polyps or adenocarcinoma. Predictive performance of serum Hcy to detect lesions was assessed using logistic regression and diagnostic accuracy measures, including models adjusted for age and sex. RESULTS Median Hcy levels rose progressively with lesion severity, reaching 15.3 μmol/L in adenocarcinoma (P < 0.001). Higher levels were also observed in men and individuals aged 65 or older. A threshold above 15 μmol/L showed good sensitivity (76.6%) and positive predictive value (87.2%) for detecting adenocarcinoma. When combined with age and sex, predictive accuracy improved (area under the receiver operating characteristic curve = 0.706). Based on these findings, we propose a three-tier triage system: Green (≤ 12 μmol/L in both sexes, colonoscopy within three months), Yellow (> 12-15 μmol/L in men, intervention within one month and red (≥ 15 in either sex or > 12 μmol/L in women, immediate colonoscopy). CONCLUSION Serum Hcy is a clinically useful biomarker for identifying high-risk colorectal lesions and cancer, particularly when interpreted in combination with age and sex. This composite model improves predictive accuracy and enables a structured three-tiered triage system that supports faster colonoscopy scheduling for at-risk groups. The traffic light approach offers a low cost, scalable strategy to reduce delays and optimize resource use in CRC screening, especially in public health systems with limited endoscopic capacity.