An implantable cardioverter defibrillator with atrial therapies (ICD-ATs) is an effective therapy to manage atrial tacharrhythmias. Acceptance of this therapy is limited by atrial shock related anxiety and discomfort. Inhaled nitrous oxide (N2O) is a potent sedative-analgesic-anxiolytic agent that may mitigate shock discomfort and anxiety and improve patient ICD-AT acceptance. ICD-AT patients with more than one ambulatory atrial shock within 12 months were enrolled and grouped by ICD-AT shock method; awake (n = 9) or asleep (n = 4) when ambulatory ICD-AT shock is delivered. A baseline questionnaire assessed the most recent ambulatory ICD-AT shock (3 +/- 3 months). A 65% N2O/35% O2 mixture was inhaled for 4 minutes followed by an ICD-AT test shock (18 +/- 8 J). The test shock mimicked the awake shock method. The test shock experience during N2O was evaluated via questionnaire immediately following and 24 hours after the shock. Shock related anxiety, intensity, pain, and discomfort were assessed using a ten-point rank scale. Baseline test shock scores were similar between the shock method groups. In the awake shock method group, N2O greatly reduced preshock anxiety by 48% (6.4 +/- 2.4 to 3.3 +/- 2.0, or), and shock related intensity (5.9 +/- 3.1 to 3.3 +/- 2.5), pain (5.0 +/- 2.6 to 2.0 +/- 2.1), and discomfort (5.6 +/- 2.4 to 1.3 +/- 1.4) from baseline values by 45%, 60%, and 78% (P < 0.05), respectively. The asleep shock method group reported no changes in shock related anxiety, intensity, pain, or discomfort. Atrial shock concern, assessed via a five-point rank scale (5 = extreme concern) was improved by N2O but only in the awake group (3.1 +/- 1.0 baseline to 1.6 +/- 0.5 N2O, P = 0.008). There were no adverse events with N2O and patients fully recovered within 5 minutes after N2O. In conclusion, 65% N2O greatly reduced shock related pain and discomfort, and significantly reduced atrial shock concern but only in the awake shock method group. The benefits of N2O therapy may expand the use and acceptability of ICD-AT therapy into a larger atrial fibrillation cohort.