This study was performed to compare the effects of a vapocoolant spray and a eutectic mixture of local anesthetics (EMLA) cream on reducing pain during intra-articular (IA) injection of the shoulder. Double-blind randomized placebo-controlled clinical trial. University hospital. Patients (N=63) who underwent IA injection of the shoulder joint were randomized into the spray group, EMLA group, or placebo group. Placebo cream+vapocoolant spray (spray group), EMLA cream+placebo spray (EMLA group), or placebo cream+placebo spray (placebo group) before IA injection. A 100-mm visual analog scale (VAS) for injection pain and 5-point Likert scales for participant satisfaction and preference for repeated use were administered immediately after IA injection. The VAS scores for pain during IA injection were 30.0 (95% CI, 19.7-41.2) in the spray group, 50.0 (95% CI, 37.7-63.0) in the EMLA group, and 53.8 (95% CI, 41.6-65.0) in the placebo group (F=6.403, P<.01). The spray group showed significantly better Likert scale scores than the placebo group for participant satisfaction (P=.003) and preference for repeated use (P<.001). Vapocoolant spray was effective in reducing pain during IA injection of the shoulder. Copyright © 2020 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.