A corticosteroid flare reaction is a well-described phenomenon that causes significant pain and dysfunction. The paucity of literature impedes decision making regarding which corticosteroid to use for shoulder injection. The purpose of this study was to compare methylprednisolone acetate (MPA) and triamcinolone acetonide (TA) injections in the glenohumeral joint and/or subacromial space in terms of efficacy and the incidence of steroid flare reactions. In this prospective, interrupted time series, parallel study, patients received injections in the glenohumeral joint and/or subacromial space. MPA and TA were used during 2 discrete 3-month periods. The injections consisted of 2 mL of lidocaine, 2 mL of bupivacaine, and 80 mg of either MPA or TA. Visual analog scale (VAS) pain scores were recorded immediately before injection; 1-7 days after injection; and 3, 6, and 12 months after injection. The primary outcome was the incidence of a steroid flare reaction, defined as a post-injection increase in the VAS score by ≥2 points. The secondary outcome was injection failure, defined as a post-injection VAS score greater than the baseline score or the need for another intervention. We used linear mixed models with a patient-level random intercept to identify the mean VAS score change for TA injections in the first week after injection. MPA or TA shoulder injections were administered in 421 patients; of these patients, 15 received bilateral-joint injections whereas 406 received a single-joint injection, for a total of 436 injections (209 MPA and 227 TA injections). Pain scores in the first week after injection were available for 193 MPA and 199 TA injections. Significantly more patients in the MPA cohort reported flare reactions compared with the TA cohort (22.8% vs. 4.0%, P<.001) during the first week after injection. In the first week after injection, the mean VAS score of patients receiving TA injections was 1.05 (95% confidence interval, 0.47-1.63) lower than that of patients receiving MPA injections when adjusted for age, sex, race, pain type, surgeon type, and injection site. At 3 months, surveys for 169 MPA and 172 TA injections were completed, with no significant difference in the rate of injection failure for MPA vs. TA (42.6% vs. 36.1%, P=.224). Treatment failure rates were significantly higher for MPA than for TA at 6 months (78.44% vs. 62.5%, P<.001) but not at 12 months (81.18% vs. 81.42%, P=.531.) CONCLUSION: TA injections resulted in a >5-fold reduction in steroid flare reactions, with statistically superior 6-month efficacy rates, compared with MPA injections. This study supports TA as a more viable corticosteroid option for shoulder injection.