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Despite its effectiveness in treating primary axillary hyperhidrosis (PAH), topical botulinum toxin type A (BTX-A) is highly resistant to transdermal absorption. Topical BTX-A liposomal cream is recommended as a novel, noninvasive modality to enhance skin penetration.To evaluate the efficacy and safety of topical BTX-A liposomal cream in comparison with liposomal vehicle cream alone in the treatment of PAH.A prospective, randomized, double-blinded, split-site study was conducted in 20 subjects, aged 18 to 50 years, all of whom had symmetrical axillary sweating with Hyperhidrosis Disease Severity Scale scores between 2 to 4. All subjects were double-blinded to treatment regimens and randomly given 2 bottles, one containing topical BTX-A liposomal cream and one containing the vehicle cream without BTX-A, to be applied consistently to the same axilla nightly for 7 consecutive days. Clinical improvement and adverse reactions were evaluated at every follow-up visit.Axillary skin treated with topical BTX-A demonstrated superior sweat reduction and patient satisfaction to vehicle cream–treated axillary skin, with clinical and statistical significance, at baseline, weeks 2, 4, 6, and 8 of follow-up, without adverse effects.Topical BTX-A liposomal cream pharmaceutically enhances drug delivery, is painless, cost-effective, and overall an innovative treatment of PAH.