To date, the primary objective of phase I trials has been to safely select the maximum tolerated dose (MTD) of a drug or drug combination for utilization in subsequent trials. Although conventional cytotoxic chemotherapy is generally more effective at the MTD than molecularly targeted agents (MTAs), recent single-institution data suggest that molecularly targeted agent may not require an MTD for efficacy. We analyzed patient outcome results in MTA phase I trials at multiple institutions throughout North America sponsored by the National Cancer Institute's Cancer Therapy Evaluation Program. We retrospectively collected and analyzed data on patients treated on monotherapy phase I trials investigating novel MTAs with a defined MTD from 2000 to 2009. Logistic regression analysis was used to test whether there was an increase in the probability of a response as dose increased. A Cox proportional hazards model was used to determine if overall survival increased with increasing dose. All statistical tests were two-sided. We analyzed 1908 patients treated on 55 eligible clinical trials. The probability of both overall response (complete response plus partial response) and overall survival increased with increasing dose (odds ratio for increased response = 1.56, P = .10; hazard ratio for death = 0.37, P = .008) when controlling for study as a covariate. Patients treated in the context of phase I trials with MTAs continue to derive reasonable clinical benefit. Contrary to other single institution data, our data suggest clinical benefit in terms of increasing response and overall survival with increasing dose.