Intramuscular injection of botulinum toxin type A is a first-line pharmacotherapy for adults with upper limb spasticity (ULS). However, reemergence of symptoms within 12 weeks of treatment is common and longer-lasting treatments are needed. To evaluate the efficacy and safety of three doses of DaxibotulinumtoxinA for Injection (DAXI) for treatment of ULS in adults with stroke or traumatic brain injury. Intramuscular injections of placebo (N = 24), DAXI 250 U (N = 22), DAXI 375 U (N = 19), or DAXI 500 U (N = 18) to the suprahypertonic muscle (SMG) and other muscle groups. Randomized, double-blind, placebo-controlled study. Twenty-six study centers across the United States. Eighty-three adult patients with ULS were randomly assigned to each treatment group and followed for up to 36 weeks. Co-primary endpoints were the Modified Ashworth Scale (MAS) score change from baseline in the designated SMG and Physician Global Impression of Change (PGIC) at Week 6. The mean changes from baseline in MAS score for the designated SMG for placebo and the DAXI 250 U, 375 U, and 500 U groups were -0.6, -0.9, -0.9, and -1.8, respectively, at Week 4 and -0.8, -0.9, -1.0, and -1.5, respectively, at Week 6. Statistically significant improvement in MAS score compared with placebo was reported only for the 500 U dose (Week 4: p < .001; Week 6: p = .049). Significant improvements in PGIC ratings compared with placebo were reported for DAXI 375 U (p = .015) and DAXI 500 U (p = .009) at Week 4 but not for any DAXI doses at Week 6. All DAXI doses were well tolerated with no trend toward more adverse events with increased dose. Results from this Phase 2 study indicate that DAXI 500 U is effective and well tolerated for treatment of adults with ULS.