Objective <p>Primidone (PMD) is a first-line treatment option for essential tremor (ET) but its use involves a risk of acute neurotoxic manifestations after the first dose. Our aim was to assess the prevalence of acute PMD intolerance in patients with ET and the potential protective effect of phenobarbital (PB) pre-treatment.</p> Methods <p>This retrospective study compared the frequency and severity of acute intolerance after a first dose of PMD (62.5&#xa0;mg) in ET patients started on treatment without previous exposure to PB or after PB pre-treatment (10&#xa0;mg/day for 2–3 weeks). Intolerance manifestations and their severity were assessed on a visual analogue scale.</p> Results <p>Twenty-five patients reported symptoms of acute intolerance to PMD, particularly somnolence, ataxia/unsteadiness, confusion, dizziness and nausea/vomiting. The prevalence of neurotoxic symptoms was 82% (23/28) among patients unexposed to PB compared with 17% (2/12) among those pre-treated with PB (<i>p</i> = 0.0002). Compared with no previous PB exposure, pre-treatment with PB was also associated with fewer number of adverse effects per patient (<i>p</i> = 0.0003) and lower severity scores (<i>p</i> = 0.0004). Two patients who could not tolerate PMD when administered without previous PB exposure reported no adverse effects when re-challenged after PB pre-treatment.</p> Conclusions <p>Pre-treatment with PB minimizes the occurrence of acute intolerance to PMD, most likely due to functional cross-tolerance. The option of receiving low-dose PB for a short period before starting on PMD should be offered to ET patients in whom PMD therapy is indicated. PB-pre-treatment should also be considered whenever occurrence of acute intolerance prevented continuation of PMD therapy.</p>