Tissue biopsy remains the conventional technique for tumor genotyping. The main limitations are it is invasive and provides only partial snapshot during disease progression. Liquid biopsy approaches via plasma and urine are possible alternatives, and the current study aims to provide comparative analyses for plasma and urine derived disease genotyping. Blood and urine specimens were collected from 150 individuals with metastatic colorectal cancer (mCRC). Patients had multiple metastases and advanced stages of cancer. Common genetic mutations including KRAS and BRAF genetic abnormalities were evaluated. Patients were also serially monitored and compared. In all cases, plasma and urine cell free DNA were successfully recovered and were of good quality for genetic analysis. Median recovered DNA from both urine and plasma samples were higher in mCRC patients than healthy volunteers indicating disease associations. Among the identified mutations, matched tumor tissue profiles compared to results from plasma ctDNA was 92%. For urine cell free DNA, the concordance among the identified mutations was 91%. Both sample types were closely matched to reference standards of tissue biopsy and indicated good clinical utility. Serial measurements indicated trends within each patient group that was linked with disease outcome. In the current study, our data indicated that both plasma and urine cell free DNA can be utilized to address possible disease progression in colorectal cancer patients. More importantly, this also provide risk stratifications that correlated to disease outcome. This can potentially aid in early clinical intervention for patients with possibly worse outcomes.