Background: Practice variation contributes to the high cost of healthcare and wasteful spending; by contrast, adherence to evidence-based (EB) clinical guidelines is advocated to improve quality and potentially lower cost. We sought to estimate the average cost per patient associated with unjustified deviations from EB national standards for use of chemotherapy, supportive drugs, and radiotherapy. Methods: The ITA Partners/eviti, Inc. database of oncology treatment plans (TPs) reviewed for payers for adherence to national guideline recommendations (e.g. ASCO, ASTRO, NCI, NCCN Compendium, FDA) was used to calculate the variance in cost between submitted TPs with unwarranted deviations from EB standards and EB care. For prospective reviews, the final EB treatment given was known and for retrospective reviews, the variance was estimated based on the EB alternative with the lowest cost. AWP pricing was used to calculate chemotherapy and supportive drug costs, and Medicare pricing for radiotherapy. First order savings were calculated. An annual trend of 8% was applied from the mid-data period to 2013 (Milliman Client Report 2010). Results: From March 2009 to March 2012, a total of 2775 consecutive patients had TPs submitted and of these, 730 patients had unjustified, non-EB TPs. All cancer types, stage and treatment intent (curative, non-curative) were included. The cost of EB treatment was less than the submitted TP for 622 (85%) patients, more for 9 (1%), and zero (could not be taken due to payer plan definitions) for 99 (14%). Descriptive statistics for the cost per patient of non-EB TPs trended to 2013 showed: mean $25,579, median $13,882, standard deviation $40,958. Conclusions: In this unselected population comprising all cancers, 26% had TPs that did not conform to EB standards or could not be medically justified. Our conservative estimate of the average per patient overspend (first order) on inappropriate treatment validates the potential for quality care to lower cost and deliver huge value to patients, physicians, and payers.