OBJECTIVE To describe the possible development of antiarrhythmic resistance to cifenline, an investigational Class I agent. METHODS Forty patients with chronic ventricular premature depolarizations (VPDs) underwent dose-ranging studies with cifenline, an investigational Class I antiarrhythmic agent. Patients had a minimum of 30 VPDs/h detected by ambulatory electrocardiographic (ECG) monitoring over a 48-hour baseline placebo lead-in period. Twenty-two patients (55 percent) who initially responded received long-term cifenline therapy. Ambulatory ECG monitoring over 24 hours was repeated during active cifenline therapy at three-month intervals and during placebo reintroduction at six-month intervals. RESULTS After an average follow-up of 28 months, VPD frequency during cifenline therapy was similar to that during initial baseline placebo therapy in 8 of the 22 patients (36 percent) who initially responded. Placebo reintroduction following cifenline failure showed a VPD frequency similar to that with active therapy. All patients had further cifenline dosage increases without success. Plasma cifenline concentrations increased in all patients and were in the high therapeutic range. All 8 patients were switched to other Class I antiarrhythmic agents with successful VPD suppression during treatment with the first alternative drug. CONCLUSIONS We conclude that antiarrhythmic resistance occurred with cifenline in these patients as (1) initial efficacy was established for a minimum of two years, (2) VPD frequency was similar during cifenline therapy and placebo reintroduction, (3) cifenline therapy failure continued despite further dosage titration, and (4) alternative Class I antiarrhythmic therapy was successful in all patients. Repeat intermittent ambulatory ECG monitoring is necessary not only to assess the continued need for antiarrhythmic drug therapy, but also to establish continued long-term efficacy.