The authors determined the effect of acute and chronic aminophylline treatment on the arrhythmogenicity of epinephrine during halothane anesthesia. The dose of epinephrine required to achieve an arrhythmia threshold (ADE) was determined in nine unpremeicated dogs anesthetized with halothane (1.5% v/v) in oxygen (A0). Aminophylline was then infused to achieve and sustain a therapeutic theophylline level (mean ± SD) of 17 ± 2 μg.m−1(A1), at which time the ADE was reassessed. The aminophylline infusion regimen was then adjusted to provide a supratherapeutic level of theophylline of 34 μg. m−1(A2) and the ADE was reassessed. In an additional seven dogs the ADE was assessed before and after 6 weeks of oral aminophylline treatment that yielded a plasma theophylline level of 18 ± 3 μg. ml−1. The ADE was significantly (P< 0.01) reduced from a basal value (mean ± SD) of 2.63 ± 0.97 μg. kg.−1min−1to 1.39 ± 0.47 in the A1state. There was no further decrement in the ADE at the A2state (1.17 ± 0.36). The plasma epinephrine level at the arrhythmia threshold decreased commensurately from 50.7 ± 40.2 ng.ml−1(A0) to 20.0 ± 7.9 and 19.2 ± 7.6 in the A1and A2states, respectively (P< 0.01). In contrast to these acute treatment experiments, neither the ADE (2.65 ± 0.95vs.2.97 ± 1.49 μg. kg−1. min−1) nor the plasma epinephrine levels at the arrhythmia threshold (47.2 ± 13.7vs.51.1 ± 22.0 ng. ml−1) were different after chronic aminophylline treatment. It is concluded that an important arrhythmia-enhancing effect is induced by a clinically relevant dose of acute intravenous aminophylline administration in a canine halothane-epinephrine arrhythmia model. However, this effect is reversed following chronic aminophylline treatment. The authors speculate that, in the acute state, the antiadenosine action of aminophylline potentiates the halothane-epinephrine arrhythmia interaction and that compensatory mechanisms normalize this effect following chronic aminophylline administration.