Pleomorphic liposarcoma (PLPS) is a recalcitrant soft‐tissue sarcoma (STS) subtype in need of transformative therapy. We have previously established a patient‐derived orthotopic xenograft (PDOX) model, of PLPS with PDGFRA amplification, using surgical orthotopic implantation. In the current study, the PLPS PDOX model was randomized into 3 groups of 7 mice each: untreated control; doxorubicin (DOX)‐treated; and treated with Salmonella typhimurium A1‐R (S. typhimurium A1‐R) expressing green fluorescent protein (GFP). Tumor volume and body weight were monitored during the treatment period. The PLPS PDOX was resistant to DOX. In contrast, the PLPS PDOX was highly sensitive to S. typhimurium A1‐R. There was no significant body‐weight loss among these 3 groups. Fluorescence imaging demonstrated that S. typhimurium A1‐R‐GFP was very effective to target the PLPS PDOX tumor. The current study demonstrates that a PLPS PDOX, resistant to first‐line therapy DOX, was highly sensitive to tumor targeting S. typhimurium A1‐R. Tumor‐targeting Salmonella typhimurium A1‐R‐GFP of the PLPS PDOX. S. typhimurium, expressing green fluorescent protein (GFP), was cultivated in serial dilution from supernatants of tumor homogenates by mincing tumor tissue on agar medium. Grown colonies of bacterial were imaged by GFP fluorescence. Fluorescent bacteria were detected at all dilutions in the tumor treated with S. typhimurium A1‐R. Scale bar: 10 mm, 2.5 mm at high magnification. BF: Bright field, GFP: Green fluorescent protein.