Botulinum toxin (BTX) is a well-established, widely used, effective treatment for primary axillary hyperhidrosis (PAH). Recently, the off-label use of letibotulinumtoxinA (LetiBTX-A), including treating movement disorders and aesthetic purposes, has been dramatically increasing due to its good efficacy. The authors hypothesized that the effectiveness of LetiBTX-A for the treatment of PAH is non-inferior to that of onabotulinumtoxinA (OnaBTX-A) which is the only US Food and Drug Administration approved BTX for severe axillary hyperhidrosis. A prospective, double-blinded, split-sided, randomized controlled trial was conducted on 30 participants with moderate to severe PAH (≥2 hyperhidrosis disease severity scale (HDSS) score). Axillae of each participant was randomly assigned to receive LetiBTX-A 50 U or OnaBTX-A 50 U. Outcome was assessed 1 month after injection. All 30 participants with a mean (SD) age of 34.44 (7.82) completed the study. At 1 month after injection, the proportion of subjects who have ≥2-point improvement from baseline HDSS score in LetiBTX-A (93.33%) and OnaBTX-A (93.33%) group was no different. More than 50% reduction of hyperhidrosis area was observed at both LetiBTX-A and OnaBTX-A-treated axillae without statistically significant difference (LetiBTX-A, 68.13%; OnaBTX-A, 65.67%; P = 0.393). Additionally, participants were equally satisfied with both LetiBTX-A and OnaBTX-A-treated axillae (P = 1.000). The mean (SD) onset of action was 1.700 (1.393) days for LetiBTX-A and 1.733 (1.388) days for OnaBTX-A (P = 0.317). Comparable procedure-related pain was observed between the 2 groups. No significant adverse events were reported. According to the findings, it can be implied that LetiBTX-A and OnaBTX-A have comparable effectiveness and safety for the treatment of PAH.