Purpose Regional anesthesia may have immediate postoperative advantages compared with general anesthesia, but its impact on post-discharge outcomes is poorly described. Our objective was to measure the association between regional anesthesia and outcomes after ambulatory shoulder surgery. Methods We conducted a historical cohort study at The Ottawa Hospital. Adults C 18 yr old having elective ambulatory shoulder surgery from January 1, 2011 to December 31, 2016 were included. Using one-to-many coarsened exact matching (CEM) to adjust for potential confounders, we matched peripheral nerve block (PNB) patients to those without a PNB. Within the matched cohort, we assessed whether PNBs were associated with our primary composite outcomes, comprising unplanned admissions, emergency department visits, readmissions, or death within 30 days of surgery. Results There were 1,623 patients who met the inclusion criteria; PNBs were placed in 1,382 (85.2%) patients. CEM matched 211 patients who did not receive a PNB to 950 patients with similar characteristics who did receive a PNB (n = 1,161; 71.5% of total cohort). In patients who received a PNB compared with those who had no PNB, there was no difference in risk of composite outcome (relative risk, 1.58; 95% confidence interval [CI], 0.83 to 3.01), or hospital costs (ratio of means 0.73; 95% CI, 0.21 to 2.49). Conclusion Peripheral nerve blocks in ambulatory shoulder surgery were not associated with a significant difference in a composite of adverse postoperative outcomes. Nevertheless, given the lower than expected incidence and moderate effect size associating PNBs with post-discharge events, future large prospective trials are needed to assess post-discharge outcomes. Trial registration www.clinicaltrials.gov (NCT03309 644). Registered 13 October 2017.