Abstract Background: Over the last 30 years, adolescent and young adult (AYA, 15-39 years of age) patients (pts) with cancer have experienced smaller improvements in 5-year survival compared to younger and older pts. One reason is their historically lower rate of participation in clinical trials (~3% AYA vs. 10% in pts > 40 years of age in adult cancer centers). A histology-agnostic trial provides greater opportunity for the AYA population and may improve accrual. The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH; NCT0246506), a phase II precision medicine trial evaluating targeted therapy in adult pts (3 18 years old) based on molecular abnormalities in a tumor-agnostic fashion, has been open since 2015. Jointly developed and coordinated by NCI and ECOG-ACRIN and open through the NCI National Clinical Trials Network and the NCI Community Oncology Research Program at more than 1100 academic and community sites, this trial screened 6801 pts for 39 independently-accruing targeted treatment subprotocols. We reviewed the AYA data from the NCI-MATCH trial, which, due to eligibility criteria, does not include pts age 15-17. Materials and Methods: AYA pts age 18-39 with treatment-refractory malignancies (solid tumor, lymphoma, or myeloma) who were (a) eligible for a screening biopsy on the NCI-MATCH trial (screening cohort [SC]) or (b) had an actionable mutation previously identified through clinically indicated sequencing at a CLIA-approved and NCI-MATCH–accepted laboratory (outside assay cohort [OAC]) were eligible for MATCH AYA analysis. Results: Of the 6801 pts screened for NCI-MATCH, 373 were AYA pts age 18-39 (5.5%). Within the SC, 93.5% (300/321) of AYA pts were successfully biopsied, vs. 92.9% of those age 40+ (5240/5640); 35.7% of the SC AYA vs. 39.6% of the 40+ pts had a study-eligible actionable mutation, and 17% (51/300) of AYA pts vs. 17.8% (934/5240) of those 40+ were subsequently assigned to treatment. Of the 401 pts in the OAC, 30 (7.1%) were AYA; 24/30 (80.0%) of AYA OAC pts were assigned to treatment vs. 87.6% (332/379) of OAC pts age 40+. Screening enrollment data show that at Lead Academic Participating Sites (LAPS), a higher percentage of AYA pts were enrolled compared to pts age 40+ (32.8% [113/344] vs. 24.3% [1472/6047], respectively). In contrast, at NCORP sites, a higher percentage of 40+ pts was enrolled relative to AYA pts (43.8% [2647/6047] vs. 35.8% [123/344], respectively). Among the top histologies enrolled (aside from colon, breast, ovarian) were soft tissue sarcoma other than rhabdomyosarcoma, primary CNS tumors, and liver and hepatobiliary, cervical, and neuroendocrine cancers. Conclusions: There were no statistically significant differences between AYA and older (40+) pts in the number who underwent successful biopsies, the prevalence of tumor actionable mutations, or the number of pts assigned to or who received study treatment. AYA pts were more likely to have been enrolled at a LAPS than a NCORP site, consistent with the AYA population being referred to LAPS upon progression from first-line treatment. Enrollment of the AYA in adult cancer centers in the NCI-MATCH trial was higher than the historical 3%: 5.5% in the SC and 7.1% in the OAC. As more tissue-agnostic studies become available in nationwide trials, AYA participation in clinical trials may increase. Citation Format: Alice P Chen, Shuli Li, Brent Coffey, James V Tricoli, Stanley R Hamilton, Mickey P Williams, Edith P Mitchell, David Patton, Robert J Gray, Lisa M McShane, Lawrence V Rubinstein, Carlos L Arteaga, Peter J O'Dwyer, Lyndsay N Harris, Barbara A Conley, Keith T Flaherty. Adolescent and young adult (AYA) cohort of the NCI MATCH clinical trial (EAY131) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A089. doi:10.1158/1535-7163.TARG-19-A089