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With efficient transduction across most cell types and larger packaging capacity, Adenovirus 5 (Ad5) makes an attractive choice as a viral vector. However, a reported past mortality and known immunogenicity cast doubt on the safety of its use. An online database search was performed for all clinical trials administering intratumoral injection of gene therapy packaged in Ad5, being conducted in the United States, and using the Common Terminology Criteria for Adverse Events (CTCAE). Studies with unclear adverse events (AE) were excluded. The primary outcome collected was grade ≥3 (AE). Analyses were performed using Fisher's exact test. Thirty-nine prospective clinical trials across a variety of cancers were identified: 14 studies of therapeutic Ad5 alone, 12 with chemotherapy, 16 with radiation, and 11 with surgery. There were 3 mortalities out of 756 patients (0.4%), which were most likely unrelated to Ad5: 1 due to hypoxic encephalopathy, 1 due to splenic vein thrombus, and 1 due to disease progression. In trials that reported total AE (grades 1–5), there were 284 (10.3%) grade ≥3 AE out of 2,745 total AE in 477 patients. The overall life-threatening (grade 4) AE rate was 1.4% (34/2,425 AE in 428 patients). Overall, the most frequent grade ≥3 AE were lymphopenia (20.6% in 14 trials, 209 patients), dyspnea (8.7% in 11 trials, 208 patients), and neutropenia (8.6% in 12 trials, 174 patients). The most frequent grade 4 AE were neutropenia (4.6%), lymphopenia (3.3%), and leukopenia (3.1% in 13 trials, 192 patients). Our analyses demonstrated relative overall safety of Ad5 and warrant re-evaluation for the use of Ad5 as a delivery vector for gene therapy products. [ABSTRACT FROM AUTHOR]