Purpose: To prospectively determine optimal parameters with which to achieve defined large target zones of coagulation by using irreversible electroporation (IRE) with four-electrode arrays and the time needed to achieve this treatment effect in an in vivo animal model. Materials and Methods: This study was approved by the animal care and use committee. Ultrasonography (US)-guided IRE ablation (n = 90) was performed in vivo in 69 pig livers with an array of four electrodes (18 gauge) and an electroporation generator. Cardiac-gated 100-μsec IRE pulses were applied sequentially between the six sets of electrode pairs at 2250-3000 V. Multiple algorithms of energy deposition and electrode configuration were studied, including interelectrode spacing (1.5-2.5 cm), number of IRE pulses applied consecutively to each electrode pair (10, 20, 50, and 100), and number of times per cycle each electrode pair was activated (one to 10). Resultant zones of treatment were measured with US 1.5-3 hours after IRE and confirmed at gross and histopathologic examination. Data and ablation times were compared to determine the optimal algorithms with which to achieve 4-7-cm areas of treatment effect in the shortest time possible. In addition, the IRE current applied was correlated with ablation size. Data were analyzed by using analysis of variance with multiple comparisons, t tests, or nonparametric statistics. Results: For 2.5-cm spacing, ablation diameter was increased by increasing either the overall time of energy application or the number of cycles of 20 pulses (P <.01 for both). IRE application of less than four cycles (or continuous IRE application of 100 pulses) did not result in contiguous ablation. However, sequentially increasing the number of cycles of IRE from four to 10 increased both the electrical current applied (from 14.4 A ± 0.4 to 17.6 A ± 0.7, P =.0004) and ablation diameter (from 5.6 cm ± 0.3 to 6.6 cm ± 0.3, P =.001). Although division of application into cycles did not alter coagulation at 2.0- and 1.5-cm spacing, application of energy to diagonal electrode pairs increased coagulation. Thus, one 100-pulse cycle (11.0 minutes ± 1.4) produced 4.8 cm ± 0.3 of ablation for 2.0-cm spacing with diagonal pairs but only 4.1 cm ± 0.3 of ablation without diagonal pairs (7.5 minutes ± 1.0, P <.03 for both). Conclusion: With four-electrode arrays, IRE can create large contiguous zones of treatment effect in clinically acceptable ablation times; parameters can be tailored to achieve a wide range of ablation sizes. Cyclical deposition of IRE application is beneficial, particularly for larger interprobe spacing, most likely owing to alterations of electrical conductivity that occur after successive applications of IRE energy.