Background: Stakeholders derive many benefits from cancer clinical trials, including guidance for future oncologic treatment decisions. However, whether enrollment in cancer trials also improves patient survival independently of trial outcomes remains underinvestigated. We hypothesized that cancer trial enrollment is not associated with patient survival outcomes. Study Design: Using the 2002 to 2008 California Cancer Registry, we identified 555,469 patients with stage I to IV solid organ tumors. Baseline characteristics were compared by trial participation status. Logistic regression determined predictors of trial enrollment. Multivariate Cox proportional hazards regression examined the impact of trial participation on overall and cancer-specific mortality with adjustment for covariates. Results: Only 0.33% of our cohort was enrolled in clinical trials. Trial participants were likely to be younger than 65 (odds ratio [OR] 2.13; 95% CI 1.90 to 2.38), Hispanic rather than non-Hispanic white (OR 0.78; 95% CI 0.67 to 0.90), and have breast cancer (OR 3.14; 95% CI 2.62 to 3.77). Multivariate survival analyses demonstrated that enrollment in cancer trials predicted a lower hazard of death. However, when stratified by disease site, this survival benefit was observed only in lung, colon, and breast cancers. Sensitivity and interaction analyses confirmed these relationships. Conclusions: In this first population-based study examining trial effect in solid organ cancers, enrollment into cancer trials predicted lower overall and cancer-specific mortality among common cancer sites. Although these findings may demonstrate a survival benefit due to trial enrollment, they likely also reflect the favorable attributes of trial enrollees. Once corroborated, stakeholders must consider broader cancer trial designs representative of the cancer burden treated in the real world. © 2013 by the American College of Surgeons.