Retrospective and single-arm prospective studies have reported clinical benefit with neoadjuvant imatinib for GISTs. In the absence of randomized Phase III data, the impact of neoadjuvant systemic therapy (NAT) on survival compared to upfront resection (UR) remains unknown. We identified N = 16 308 patients within the National Cancer Database (2004-2016) who underwent resection of localized GIST of the stomach, esophagus, small bowel and colorectum, with or without ≥3 months of NAT. Inverse probability of treatment weighting adjusted for covariable imbalance among treatment groups. We estimated the effect of NAT on overall survival with a weighted time-dependent Cox proportional hazards model, and on 90-day postoperative mortality and R0 resection with weighted logistic regressions. Eight hundred sixty-five (5.3%) patients received NAT compared to 15 443 (94.7%) who underwent UR. Median NAT duration was 6.3 months. 53.7% of NAT patients were male vs 48.6% of UR patients, 67.3% vs 65.1% had primary gastric GIST and 72.8% vs 49.7% were at high risk. NAT patients had larger tumors and higher mitotic index. >3 months of NAT was associated with a significant survival benefit (weighted HR 0.85 [0.80-0.91]). 90-day postoperative mortality rate was 4/865 (0.5%) among NAT patients vs 346/15443 (2.2%). NAT was associated with lower odds of 90-day postoperative mortality. R0 resection rate was not significantly different between groups. In conclusion, despite higher risk features among NAT patients, this analysis suggests that NAT for localized GIST is associated with a modest survival benefit and lower risk of 90-day postoperative mortality, with no difference in likelihood of achieving an R0 resection.