BACKGROUND: Stagnant outcomes for adolescents and young adults (AYAs) 15-39 years of age with cancer are partly attributed to poor enrollment onto clinical trials. Initiatives have focused on increasing accrual, but changes at the population-level are unknown. We examined patterns of clinical trial participation over time in AYA patients with cancer. PROCEDURE: We utilized medical record data from AYAs in two population-based National Cancer Institute Patterns of Care Studies identified through the Surveillance, Epidemiology and End Results Program. Among 3135 AYAs diagnosed with non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, acute lymphoblastic leukemia (ALL), and sarcoma, we used multivariate logistic regression to evaluate patient and provider characteristics associated with clinical trial enrollment. Interaction terms evaluated variation in clinical trial enrollment across patient and provider characteristics by year of diagnosis. RESULTS: From 2006 to 2012-2013, clinical trial participation increased from 14.8% to 17.9% (P < 0.01). Adjusting for patient and provider characteristics, we found lower clinical trial enrollment among those who were older at diagnosis, diagnosed with NHL vs ALL, treated by adult hematologist/oncologists only (vs pediatric hematologist/oncologists), and of non-Hispanic Black race/ethnicity (vs non-Hispanic White) (P < 0.05 for all). Interaction analyses indicate improved clinical trial enrollment from 2006 to 2012-2013 among young adults 25-29 years of age and the uninsured. CONCLUSIONS: Although disparities in enrollment onto clinical trials remain for AYAs with cancer, our study identified increasing overall clinical trial participation over time. Further, we identify promising trends in enrollment uptake among AYAs 25-29 years of age and the uninsured.