Botulinum toxin type A (BoNT/A) improves symptoms of palmar hyperhidrosis, but some drawbacks related to its injection in the hands still persist (e.g., muscle weakness caused by drug diffusion, pain during injections, or delayed functional recovery of the hand when using wrist block). In this open, controlled, non-randomized, intra-individual clinical trial, 50 patients with severe palmar hyperhidrosis received in the same session intradermal injections of BoNT/A through a new injection technique (NA/BoNT/A) based on the use of a specific adapter for needles (PCT/IT2011/000299) in one hand, and BoNT/A injection following the anaesthetic block of the wrist (WB/BoNT/A) in the other. Several measures of efficacy and safety were evaluated both before (T0) and four weeks after the treatment (T4): disease severity improvement, sweat reduction, handgrip strength decrease, pain/discomfort during the treatment, and patient's global satisfaction. All patients were also re-evaluated through the gravimetric assessment of sweat production in both hands at T12 and T24 to compare the long-term efficacy of the two treatments. All patients were responsive to the treatments, and disease severity was significantly decreased at T4 compared to baseline (p < 0.0001). Both procedures were equally effective in reducing sweat production in the short term (p = 0.08 at T4), but WB/BoNT/A caused a higher decrease of handgrip strength compared with WB/BoNT/A at T4 (p < 0.0001). Finally, patients reported that NA/BoNT/A and WB/BoNT/A procedures were comparable for pain/discomfort (p = 0.204); however, they were globally more satisfied with the NA/BoNT/A rather than WB/BoNT/A method (p < 0.0001). No significant difference in percentage of clinical relapse at T12 and T24 was detected between hands treated via WB/BoNT/A or NA/BoNT/A (p = 0.70). The use of the described adapter to inject BoNT/A in the hands seems to lead the clinicians to obtain same therapeutic results of conventional method based on the use of anaesthetic block of the wrist. Moreover, this new injective approach seems to increase the safety of the treatment by reducing the extent of muscle weakness and is preferred by patients mostly because it makes the functional recovery of the hand faster.