The recombinant herpes zoster vaccine (RZV), approved as a 2-dose series in the U.S. in October 2017, has proven highly effective and generally safe. However, a small risk of Guillain-Barré syndrome (GBS) after vaccination was identified post-approval, and questions remain about other possible adverse events. This data-mining study assessed RZV safety in the U.S. using the self-controlled tree-temporal scan statistic, scanning data on thousands of diagnoses recorded during follow-up to detect any statistically unusual temporal clustering of cases within a large hierarchy of diagnoses. IBM Marketscan data on commercially insured persons 50+ years of age receiving RZV during January 1, 2018 - May 5, 2020 were used, with 56 days of follow-up. 1,014,329 doses were included. Statistically significant clustering was found for: unspecified adverse effects, complications, or reactions to immunization or other medical substances/care; fever; unspecified allergy; syncope/collapse; cellulitis; myalgia; and dizziness/giddiness, all within a few days of vaccination. These findings are consistent with the known safety profile of this and other injected vaccines. No cluster of GBS was detected, possibly due to insufficient sample size. This signal-detection method has now been applied to 5 vaccines, with consistently plausible results, and seems a promising addition to vaccine safety evaluation methods.