In an investigation designed to study the nature and prevalence of side effects during long‐term therapy and the degree of correlation between side effects and the drug serum level, starting in 1975, mexiletine was given to 12 patients for 4 to 128 months with a mean of 56.2 months. The patients were followed according to a strict protocol for the first 18 months of treatment and then returned to routine care. In August 1983, 5 patients had been taking mexiletine for 74 and 96 months (mean 85 months). At the latest follow‐up in April 1986, two patients were still on mexiletine therapy after 117 and 128 months of medication, respectively. A third patient died of probable digitalis intoxication just prior to follow‐up, having then been on mexiletine for 118 months, Mexiletine was well tolerated and no serious side effects were seen. In particular, there was no rise in antinuclear factor titer. The serum level of mexiletine was easily maintained within the therapeutic range. The cerebral side effects correlated closely with the drug level; the gastrointestinal with the amount of mexiletine per dose. It is concluded that mexiletine can be administered for a long time as a safe alternative to other anti arrhythmic drugs.