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Background Pediatric Phase I cancer trials are critical for establishing the safety and dosing of anti-cancer treatments in children. Their implementation, however, must contend with the rarity of many pediatric cancers and limits on allowable risk in minors. The aim of this study is to describe the risk and benefit for pediatric cancer Phase I trials. Methods and findings Our protocol was prospectively registered in PROSPERO (CRD42015015961). We systematically searched Embase and PubMed for solid and hematological malignancy Phase I pediatric trials published between 1 January 2004 and 1 March 2015. We included pediatric cancer Phase I studies, defined as “small sample size, non‑randomized, dose escalation studies that defined the recommended dose for subsequent study of a new drug in each schedule tested.” We measured risk using grade 3, 4, and 5 (fatal) drug-related adverse events (AEs) and benefit using objective response rates. When possible, data were meta-analyzed. We identified 170 studies meeting our eligibility criteria, accounting for 4,604 patients. The pooled overall objective response rate was 10.29% (95% CI 8.33% to 12.25%), and was lower in solid tumors, 3.17% (95% CI 2.62% to 3.72%), compared with hematological malignancies, 27.90% (95% CI 20.53% to 35.27%); p < 0.001. The overall fatal (grade 5) AE rate was 2.09% (95% CI 1.45% to 2.72%). Across the 4,604 evaluated patients, there were 4,675 grade 3 and 4 drug-related AEs, with an average grade 3/4 AE rate per person equal to 1.32. Our study had the following limitations: trials included in our review were heterogeneous (to minimize heterogeneity, we separated types of therapy and cancer types), and we relied on published data only and encountered challenges with the quality of reporting. Conclusions Our meta-analysis suggests that, on the whole, AE and response rates in pediatric Phase I trials are similar to those in adult Phase I trials. Our findings provide an empirical basis for the refinement and review of pediatric Phase I trials, and for communication about their risk and benefit., Jonathan Kimmelman and colleagues report findings from their meta analysis that shows that adverse effects and response rates in phase 1 cancer clinical trials are similar for children as for adults., Author summary Why was this study done? Phase I cancer clinical trials aim to determine the safety of a new drug, and present a high risk of serious adverse events with limited prospect of therapeutic benefit. National and international regulations establish limits on allowable risk for research involving children. Little is known about the level of risk and benefit in pediatric Phase I trials in oncology. We designed this systematic review with meta-analysis to establish the risk and benefit associated with pediatric Phase I studies in oncology, and to compare our results with those reported for Phase I adult studies in the literature. What did the researchers do and find? We systematically searched for pediatric Phase I cancer studies published between 1 January 2004 and 1 March 2015. We identified 170 studies with 4,604 patients meeting eligibility criteria. The pooled overall objective response rate was 10.29%, with a response rate of 3.17% for solid tumors and 27.90% for hematological malignancies. The overall rate of clearly reported fatal (grade 5) adverse events was 2.09%. The average grade 3/4 adverse event rate per person was equal to 1.32. What do these findings mean? Serious (grade 3, 4, and 5) adverse event and response rates for pediatric Phase I cancer studies were similar to those reported for adult studies. These data help to inform the assessment and ethical evaluation of, and communication about, risk for pediatric Phase I cancer protocols.