Twenty-three patients were treated for at least one month with encainide, a new antiarrhythmic drug. No patient was treated for hyperglycemia prior to encainide therapy. During encainide administration, five episodes of marked hyperglycemia (serum glucose level greater than or equal to 200 mg/dl) developed in four patients. (One patient received encainide twice.) The mean pretreatment glucose level was 190 ± 69 mg/dl and rose to 397 ± 163 mg/dl after one month of encainide therapy in patients in whom hyperglycemia developed (p <0.025). The glucose level was 111 ± 27 mg/dl in nonhyperglycemic patients before encainide administration and 108 ± 22 mg/dl after one month of encainide therapy (p = NS). There was no difference in age or encainide dosage between hyperglycemic and nonhyperglycemic patients. Treatment for hyperglycemia was given during four of the five encainide treatment periods in hyperglycemic patients. Encainide was discontinued in each of the five hyperglycemic episodes; therapeutic requirements for hyperglycemia markedly decreased. Hypoglycemic reactions to insulin occurred in two patients when encainide was stopped. Thus, encainide exacerbates hyperglycemia in some patients. These patients usually have mild hyperglycemia not requiring therapy before administration of encainide but may require insulin while receiving encainide. Treatment requirements for hyperglycemia decrease following withdrawal of encainide. The mechanism of this effect and the consequences of long-term encainide therapy on glucose metabolism are unknown.