The specific blocking of the axillary nerve has never been investigated clinically. We present four cases illustrating potential applications of the axillary nerve block in the perioperative setting and discuss possible directions for future research in this area. The axillary nerve blocks were all performed using a newly developed in-plane ultrasound-guided technique. In one patient undergoing arthroscopic shoulder surgery, we used the axillary nerve block as the only analgesic combined with propofol sedation and spontaneous breathing. Chronic shoulder pain was eliminated after the axillary nerve block in two patients. The pain score after arthroscopic shoulder surgery in these two patients remained low until termination of the nerve block. In a fourth patient, severe post-operative pain after osteosynthesis of a displaced proximal humerus fracture was almost eliminated after performing an axillary nerve block. These findings warrant larger clinical trials that investigate the pain-mediating role of the axillary nerve in the perioperative setting.