Treatment of epilepsy depends on adherence to a drug regimen as prescribed and periodic assessment of progress. Typical problems of compliance to medication and adherence to follow-up in long-term epilepsy treatment in a clinical trial were analyzed. Zero drug levels, subtherapeutic levels, variable levels and delayed dose were measures of non-compliance to the drug regimen. Missed visits and non-drug-related dropouts from the study marked non-adherence. Data from 622 patients participating in a multicenter evaluation of the efficacy and toxicity of carbamazepine, phenobarbital, phenytoin and primidone, showed generally good compliance. Only 5% of patients had zero drug levels or greater than or equal to 24 h since prior dose at 2 or more visits. Good adherence to the protocol was demonstrated by 93% attendance as scheduled. The support structure of the study and the availability of a study assistant helped many patients to prevent potential problems and convert patients into excellent adherers.