Background: Detection of circulating tumor DNA (ctDNA) following operative management for colorectal cancer (CRC) as part of molecular residual disease (MRD) assays has shown significant prognostic implications. The majority of studies examining the time to detection of cancer recurrence have been done retrospectively without the treating physician knowing the results of the assay. Limited prospective data exists regarding the probability of detecting cancer on imaging at the time of a positive MRD test following operative management of all sites of disease. Here, we analyze the association of positive MRD testing with imaging findings of recurrent or metastatic CRC using a cohort of patients that underwent prospective MRD testing. Methods: Patients with stage I-IV intestinal cancers at University of Wisconsin Carbone Cancer Center who underwent prospective Natera Signatera MRD testing following operative management of their disease were identified and consented to an IRB-approved registry protocol. Those consented patients who had a positive test without being on systemic therapy and had clinical imaging within 45 days were analyzed further. The presence of definitive cancer, indeterminate findings, and no evidence of cancer was recorded per the treating physician using standard of care clinical imaging. The presence of cancer on imaging was then correlated with the quantity of ctDNA (mean tumor molecules (MTM)/ml). Results: 163 patients with stage I-IV CRC and 1 small intestinal cancer underwent MRD testing. 30 positive ctDNA tests with imaging were available across 22 unique patients (median age 54 years (29-84) 7 females). 23 samples were in the resected metastatic setting, 5 stage III and 2 stage I. Cancer was seen on imaging in 19/30 (63%) of positive tests, indeterminate in 3 (10%) and negative for cancer in 9/30 (27%). With ctDNA levels > 10 MTM/ml (n = 7), cancer was detected on imaging in all cases. With ctDNA levels of 1-10 MTM/ml cancer was detected in 42% and at < 1 MTM/ml in 64%. A trend towards greater detection of cancer was observed when MRI or PET/CT was performed. Radiologic disease detection in patients with positive MRD analysis was higher in those with stage IV disease (70%) vs. stage I-III (43%). Conclusions: ctDNA MRD positivity is associated with high rates of detection of recurrent/metastatic CRC, especially in patients with resected stage IV disease and with a quantity of > 10 MTM/ml. Clinical imaging should be considered at the time of detection of ctDNA.