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This study combines fast magnetic resonance imaging (MRI) and model simulation of tissue thermal ablation for monitoring and predicting the dynamics of lesion size for tumor destruction. In vivo experiments were conducted using radiofrequency (RF) thermal ablation in paraspinal muscle of rabbit with a VX2 tumor. Before ablation, turbo-spin echo (TSE) images visualized the 3-D tumor (necrotic core and tumor periphery) and surrounding normal tissue. MR gradient-recalled echo (GRE) phase and magnitude images were acquired repeatedly in 3.3 s at 30-s intervals during and after thermal ablation to follow tissue temperature distribution dynamics and lesion development in tumor and surrounding normal tissue. Final lesion sizes estimated from GRE magnitude, post-ablation TSE, and stained histologic images were compared. Model simulations of temperature distribution and lesion development dynamics closely corresponded to the experimental data from MR images in tumor and normal tissue. The combined use of MR image monitoring and model simulation has the potential for improving pretreatment planning and real-time prediction of lesion-size dynamics for guidance of thermal ablation of tumors.