Purpose To characterize the performance of a 980-nm diode laser ablation system in an in vivo tumor model. Materials and Methods This study was approved by the institutional animal care and use committee. The ablation system consisted of a 15-W, 980-nm diode laser, flexible diffusing-tipped fiber optic, and 17-gauge internally cooled catheter. Ten immunosuppressed dogs were inoculated subcutaneously with canine-transmissible venereal tumor fragments in eight dorsal locations. Laser ablations were performed at 79 sites where inoculations were successful (99%) at powers of 10 W, 12.5 W, and 15 W, with exposure times between 60 and 180 seconds. In 20 cases, multiple overlapping ablations were performed. After the dogs were euthanized, the tumors were harvested, sectioned along the applicator tract, measured, and photographed. Measurements of ablation zone were performed on gross specimen. Histopathology and viability staining was performed with hematoxylin and eosin and nicotinamide adenine dinucleotide hydrogen staining. Results Gross pathologic examination confirmed a well circumscribed ablation zone with sharp boundaries between thermally ablated tumor in the center surrounded by viable tumor tissue. When a single applicator was used, the greatest ablation diameters ranged from 12 mm at the lowest dose (10 W, 60 seconds) to 26 mm at the highest dose (15 W, 180 seconds). Multiple applicators created ablation zones as large as 42 mm in greatest diameter (with the lasers operating at 15 W for 120 seconds). Conclusions The new 980-nm diode laser and internally cooled applicator effectively create large ellipsoid thermal ablations in less than 3 minutes.