To compare the efficacy and side effects of beta-blockers with intrinsic sympathomimetic activity (ISA) to those without ISA, we retrospectively reviewed patients diagnosed with neurocardiogenic syncope (NCS) as determined by head-up tilt table testing. Four hundred and thirty-one patients (mean age of 57 +/- 25 years) underwent head-up tilt table testing for syncope of unknown etiology, of which 120 patients were diagnosed with NCS; 87 of these patients were treated with beta-blocker therapy. Only 56 patients could be contacted during follow-up. Twenty-eight patients were treated with beta-blockers with ISA (acebutolol or pindolol) and 28 received beta-blockers without ISA (atenolol or metoprolol) based on physician preference and followed for up to 2 years. During the follow-up period, beta-blockers with or without ISA had comparable clinical efficacy in suppressing recurrent syncope in patients with NCS. However, beta-blockers with ISA were better tolerated and caused less fatigue (32% side effects) as compared to those without ISA (50% side effects; p = 0.23). The benefits of beta-blockers with ISA were more pronounced in patients less than 60 years old (19% side effects with beta-blocker with ISA as compared to 85% side effects with beta-blocker without ISA; p = 0.0004). Beta-blockers without ISA appear to be better tolerated and caused less fatigue in patients 65 years old or greater (20%) than in patients less than 65 years old (85%; p = 0.0002).