Purpose: To prospectively optimize multistep algorithms for largest available multitined radiofrequency (RF) electrode system in ex vivo and in vivo tissues, to determine best energy parameters to achieve large predictable target sizes of coagulation, and to compare these algorithms with manufacturer's recommended algorithms. Materials and Methods: Institutional animal care and use committee approval was obtained for the in vivo portion of this study. Ablation (n = 473) was performed in ex vivo bovine liver;final tine extension was 5-7 cm. Variables in stepped-deployment RF algorithm were interrogated and included initial current ramping to 105°C (1°C/0.5-5.0 sec), the number of sequential tine extensions (2-7 cm), and duration of application (4-12 minutes) for final two to three tine extensions. Optimal parameters to achieve 5-7 cm of coagulation were compared with recommended algorithms. Optimal settings for 5- and 6-cm final tine extensions were confirmed in in vivo perfused bovine liver (n = 14). Multivariate analysis of variance and/or paired t tests were used. Results: Mean RF ablation zones of 5.1 cm ± 0.2 (standard deviation), 6.3 cm ± 0.4, and 7 cm ± 0.3 were achieved with 5-, 6-, and 7-cm final tine extensions in a mean of 19.5 min ± 0.5, 27.9 min ± 6, and 37.1 min ± 2.3, respectively, at optimal settings. With these algorithms, size of ablation at 6- and 7-cm tine extension significantly increased from mean of 5.4 cm ± 0.4 and 6.1 cm ± 0.6 (manufacturer's algorithms) (P <.05, both comparisons);two recommended tine extensions were eliminated. In vivo confirmation produced mean diameter in specified time: 5.5 cm ± 0.4 in 18.5 min ± 0.5 (5-cm extensions) and 5.7 cm ± 0.2 in 21.2 min ± 0.6 (6-cm extensions). Conclusion: Large zones of coagulation of 5-7 cm can be created with optimized RF algorithms that help reduce number of tine extensions compared with manufacturer's recommendations. Such algorithms are likely to facilitate the utility of these devices for RF ablation of focal tumors in clinical practice.