In many patients with early stage colon cancer, management after surgical resection remains a clinical dilemma. The goal of adjuvant chemotherapy after surgery is to eradicate occult micro-metastases, if present; however, therapy is not tailored to the individual patient due to our limited ability to define risk based on standard clinic-pathologic assessment. Ultimately many apparently high risk patients would not have relapsed and some apparently low risk patients will recur, even with treatment, with no method to measure treatment effectiveness. A fundamentally different approach to defining recurrence risk and assessing benefit of adjuvant chemotherapy for patients with early stage colon cancer is urgently needed. Circulating tumour DNA (ctDNA) can be detected in the majority of patients with advanced cancer and dynamic changes in ctDNA has been shown to reflect tumour burden. We examined post-operative blood samples to identify direct evidence of minimal residual disease in the form of circulating DNA (ctDNA) that is released into the circulation from occult cancer cells that remain after surgery. While high-risk histopathologic or molecular characteristics of tumours indicate a propensity for metastasis, the presence of circulating mutant DNA molecules is direct evidence of residual disease. We report data from the first prospective, multicentre study of two large cohort of patients with stage II colon cancer and rectal cancer to test this approach. Somatic mutations in patients’ tumours were initially identified by sequencing 15 genes commonly mutated in colorectal cancer. We then designed personalized Safe-SeqS assays to quantify ctDNA in plasma samples. We found that ctDNA detection shortly after surgery ("ctDNA recurrence") nearly always indicates a later "radiologic recurrence". And importantly, the absence of detectable ctDNA predicts a very low risk of radiologic recurrence. Early data also suggests that changes in ctDNA status during adjuvant chemotherapy could provide a real time read-out of treatment benefit. Detection of ctDNA in patients after resection of early stage colorectal cancer is associated with a high-risk of disease recurrence. Serial ctDNA analyses may help inform adjuvant therapy decision-making and subsequent management of this patient group.