Background: eviCore healthcare uses the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) to support its proprietary program for medical oncology drug management. All treatment regimens assigned NCCN Category of Evidence 1, 2A, or 2B are considered NCCN-adherent treatment selections in the eviCore program. The purpose of this study was to evaluate the pattern of NCCN adherence during the first year following program launch in regional payer markets. Methods: All cancer drug treatment authorization requests submitted in month 1 and month 12 following program launch for 4 regional third-party payers representing 13 different states were included, each of whom had management of high cost oncology drugs in place prior to eviCore program launch. Month 1 data were used as a surrogate for pre-program NCCN adherence, which is an overestimate as there is significant eviCore program impact on patients initiating therapy during that time. Requests with incomplete clinical data were excluded from analysis. Included requests were stratified by month 1 or month 12 from initial program launch date for each health plan. NCCN adherence was assigned based on the results of the clinical decision support and peer consultation processes utilized by eviCore to adjudicate the treatment request. NCCN adherence rate was calculated for each subgroup and a cumulative NCCN adherence rate for all included cases was calculated using weighted average accounting for volume differences by market. Results: There were 2,028 treatment regimen requests that were fully evaluable, with 1,285 occurring in month 1 and 743 occurring in month 12 following program launch. The rate of NCCN adherence increased for each health plan during the first program year, ranging from 69%–84% in month 1 and rising to 79%–91% in month 12. The weighted cumulative NCCN adherence during month 1 for all included plans was 75% and rose to 88% at month 12 following program launch. Conclusions: Use of clinical decision support supplemented by peer consultation is an effective means of increasing oncologists’ adherence to NCCN-recommended therapies across a broad range of regional provider markets. Additional study is warranted to determine whether this methodology can be applied to NCCN Categories of Preference to direct more patients toward preferred regimens with superior efficacy, safety, and affordability to further improve quality of care and lower total medical costs.