Currently, the effect of skeletal muscle loss during neoadjuvant imatinib therapy on clinical outcomes in patients with locally advanced gastrointestinal stromal tumors (LA-GIST) remains unclear. This study aims to investigate the relationship between changes in skeletal muscle and postoperative complications, survival and tumor response in patients with LA-GIST during neoadjuvant therapy with imatinib.We retrospectively analyzed pre- and post-treatment computed tomography images of 57 GIST patients who underwent radical surgery after neoadjuvant therapy with imatinib from January 2013 to March 2019. Skeletal muscle index (SMI) was measured at the L3 vertebral level in all patients. A cut-off value (SMI < 52.3 cm2/m2 and < 38.6 cm2/m2 for men and women, respectively) published in a previous study was used to define sarcopenia. Based on gender, we defined ΔSMI (%)/250 days above 9.69% for men and ΔSMI (%)/250 days above 7.63% for women as significant muscle loss (SML). Factors associated with postoperative complications and tumor response were analyzed using logistic regression, and predictors affecting patient prognosis were analyzed using Cox regression.Of the 57 patients, sarcopenia was present before and after neoadjuvant therapy in 20 (35.09%) and 28 (49.12%) patients, respectively. It was not associated with immediate or long-term clinical outcomes. However, patients with SML during neoadjuvant therapy had a higher incidence of postoperative complications (60.00% vs. 25.00%, p = 0.008), worse pathological regression (44.00% vs. 75.00%, p = 0.017) and worse 3-year survival (Male, 68.75% vs. 95.45%, p = 0.027; Female, 66.67% vs. 100.00%, p = 0.046) than patients without SML.The development of SML during neoadjuvant therapy in LA-GIST patients, rather than pre- and post-treatment sarcopenia, is a major prognostic factor for the long-term prognosis and is also associated with recent postoperative complication rates and pathological regression.© 2022. The Author(s).