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The objective of this study is to report on our 5-year collective experience on the use of perhexiline in the UK, in patients with chronic heart failure (CHF) and/or refractory angina with respect to ‘real-life’ drug side effects and toxicity, therapeutic drug level monitoring, 5 year mortality outcomes and predictors of response to perhexiline therapy.Data on clinical history, perhexiline monitoring, follow-up, and mortality were retrospectively collated from centralized perhexiline databases from two tertiary referral centres. A total of 151 patients were on perhexiline therapy at two UK tertiary referral centres. At 3–4 months, 68.8% of patients had drug level within the therapeutic range and 20.8% were above the therapeutic range. A total of 58.9% of patients reported to have felt better on the perhexiline (responders). The presence of refractory angina was an independent predictor of response to perhexiline therapy (odds ratio 2.84, 95% confidence interval 1.28–6.32, P=0.01). Five-year mortality was non-significantly different between patients with refractory angina, CHF, or both (20.5, 31.0, and 38.4%, P=0.20, respectively).Perhexiline therapy provides symptomatic relief in the majority of patients with minimal side effects or toxicity. Careful therapeutic level monitoring for dose titration is important to prevent acute and chronic toxicity. Patients with refractory angina were more likely to be responders.