Objective: To systematically review the safety of phentolamine mesylate as a reversal agent for pulpal and soft tissue dental anesthesia. Data sources: Comprehensive search, up to August 2018, was performed in three major electronic databases. The methodologic quality of all the included studies was assessed using Cochrane Collaboration for randomized clinical trials. Results: A total of nine studies were included for qualitative and quantitative assessment. The number of events was 269 in 2,057 participants in the phentolamine mesylate group, and 179 in 1,338 participants of the control group (odds ratio 1.19; 95% confidence interval 1.03 to 1.39). In the data segregated based on age, four studies conducted on children and adolescents revealed an odds ratio of 0.68, whereas two studies on adults revealed an odds ratio of 1.58. Conclusion: There were no severe complications reported in any of the included studies, but the occurrence of adverse events (mild and moderate) was greater in the phentolamine mesylate group compared to the control group. Age has a significant effect on the possibility of adverse events with phentolamine mesylate. Keywords: local anesthetic, phentolamine, safety