Background: Botulinum toxin A (BoNT-A) is an effective treatment for axillary hyperhidrosis (AH) typically applied by multiple injection punctures. Objective: To compare the efficacy and safety of two BoNT-A injection techniques for AH. Methods: Randomized, evaluator-blinded trial, in which each axilla of the same patient received 50 U of incobotulinumtoxin A (IncoA; Xeomin), one injected intradermally using multiple punctures, the other subcutaneously by radial approach. Follow-up visits occurred after 30, 120, 180, and 270 days. Outcomes included procedure duration and pain, gravimetry and starch-iodine tests and safety. Results: Twenty-four patients with severe hyperhidrosis were included; 67% were female and mean age was 34.7 years. Radial injection was faster applied than multiple punctures (P<0.001) but showed higher pain scores (P=0.001). Pre- and post-treatment gravimetric measures showed that IncoA led to a significant sweat reduction, by both techniques, with 95% of responders (≥50% reduction from baseline) after 30 days of treatment. Similarly, Minor's test showed an excellent response (90-100% reduction) by most patients regardless of the technique used, after 30 days and sustained for at least 270 days. At most time points, there were no significant differences between the two techniques; however, multiple punctures showed a higher reduction of gravimetric measures at days 30 and 180, and of Minor's test at day 270. Treatment was well tolerated. Conclusions: IncoA is an effective and safe treatment for AH irrespective to the technique used for injection. Our study suggests that multiple punctures injection may confer better outcomes at some time points. J Drugs Dermatol. 2020;19(7): doi:10.36849/JDD.2020.4989.