Clinical signs and lesions of Taura syndrome virus (TSV) infection in Penaeus monodon have not been documented although the virus has been detected in this shrimp species by reverse transcription polymerase chain reaction (RT-PCR). This study provides the first evidence of TSV infection in P. monodon by histological and in situ hybridization (ISH) analyses. We performed experimental bioassays with groups of P. monodon using inocula of P. monodon and Litopenaeus vannamei (Th04PmTSV and Th04LvTSV, respectively), which were collected from Thailand in 2004 and found to be positive for TSV by RT-PCR. Samples of shrimp for histological and ISH analyses were collected on Days 2, 14, and 28 post-inoculation. Mortality among TSV-inoculated P. monodon appeared on Day 3, with 2 out of 10 shrimp dying. Severe necrosis of cuticular epithelial cells and lymphoid organ spheroids, indicative of acute and chronic phase lesions of TSV infection, respectively, were detected in the samples. Sequence analyses of the capsid protein 2 (CP2) gene showed that Th04PmTSV and Th04LvTSV isolates were different; however, both belonged to a phylogenetic family of Asian TSV isolates. The results of this study demonstrated that both mortality and histological lesions are associated with TSV infection in P. monodon.