The aim of this study was to evaluate the feasibility, safety and efficacy of transradial/brachial (TR/TB) carotid artery stenting (CAS) with proximal cerebral protection (PCP) as a first line of treatment of carotid artery stenosis. Among 556 patients with significant (>50% if symptomatic or >70% if asymptomatic by Doppler US) unilateral, lipid-rich carotid artery stenosis undergoing TR/TB CAS, 137 (24.5%) deemed at high-risk for periprocedural cerebral embolization were scheduled for PCP with Mo.MA Ultra or Mo.MA mono-balloon. In patients with very complex anatomy the standard technique was modified loading the Mo.MA catheter without mandrel on two-wire system (so called 'No MAndrel 2 wire' technique, No.MA2) to increase support and deliverability. Device, technical and procedural successes both acute and at follow-up were the main outcomes. Mean patients' age was 74±7 years (93% male), 15% were symptomatic and 59.6% owned 'high-surgical-risk' features. Stenosis degree was 85±7% with soft composition in all (by CT-angiography). TR and TB approach were selected in 92 (67%) and 45 (33%) patients, respectively. Target carotid axes were right, left bovine and left non bovine in 55%, 38% and 7% of patients. Procedures were successfully completed in all patients (intention-to-treat basis) with the standard Mo.MA Ultra system in 129 patients and the Mo.MA mono-balloon in 8 patients. No.MA2 technique was succesfully used in 16 patients as 'bailout' and in 27 patients as 'first line'). Device and technical success was 97% (133/137 patients) due to crossover to femoral access in 3 cases, and Mo.MA too short to engage the ECA in 1 patient. The procedural success was 96.7% (131/137, two minor strokes). Procedural time and fluoroscopy time were increased with No.MA2 technique. One major vascular complication occurred, in the TB group, while chronic radial occlusion was detected by Doppler ultrasound in 7/92 patients (7.1%) at 372±163 days of follow-up. The event-free survival was 91% and the stroke rate was 0%. TR/TB CAS with proximal protection is a feasible, safe and effective strategy and may be considered a first line strategy in all comer patients.