Fiber structure governs the spread of excitation in the heart, however, little is known about the effects of physiological variability in the fiber orientation on epicardial activation. To investigate these effects, we used computer simulation to compare ventricular activation sequences initiated from stimulus sites at regularly spaced depths within the myocardium under varying rule-based fiber ranges. We compared the effects using four characteristics of epicardial breakthrough (BKT): location, area, shape (calculated via the axis ratio of a fitted ellipse), and orientation. Our results showed changes in the BKT characteristics as pacing depth increased, e.g., the area increased, the shape became more circular, and the orientation rotated counterclockwise, regardless of the fiber orientation. Furthermore, the maximal differences in epicardial activation from a single pacing site for location, area, axis ratio, and orientation were 1.2 mm, 74 mm 2 , 0.16, and 26°, respectively. Our results suggest that variability in fiber orientation has a negligible effect on the location, area, and shape of the BKT, while fluctuations were observed in the BKT orientation in response to the fiber fields, especially for epicardial stimulation sites. Our results suggest the fiber field orientation plays only a minor role in activation simulations of ectopic beats.