Most gastrointestinal stromal tumors (GISTs) occur in the tubular gastrointestinal tract, but some present apparently outside the GI-tract. In this study, we analyzed 112 GISTs located in the retroperitoneum. These tumors occurred in 55 women and 57 men with a median age of 65 years (range: 21-89 years). Based on clinically or histologically detected connections to GI-tract, 15 tumors were considered likely of gastric, 9 duodenal, and 13 of small intestinal origin. The remaining cases were categorized by location as peripancreatic (n = 25), pelvic (n = 11), mesenteric (n = 4), and of unspecified/miscellaneous sites (n = 35). The tumors varied in size 3-35 cm (median, 15 cm) and by mitotic rate per 5 mm2, 0- >100 (median 10). Histologically the tumors apparently arising outside the GI-tract had features of intestinal (n = 41) and gastric GISTs (n = 25); 9 cases had indeterminate histology. The histologic variants included spindled, epithelioid, vacuolated, nested and myxoid potentially simulating other tumors such as liposarcoma and solitary fibrous tumor. Most GISTs were KIT-positive (106/112 cases), and the remaining 6 tumors were Dog1/Ano1-positive. Five cases showed focal nuclear positivity for MDM2. KIT mutations were detected in 42/59 cases, and PDGFRA mutations in 4/16 KIT wild-type and 3/5 of the KIT-negative tumors analyzed. One pelvic retroperitoneal GIST was SDH-deficient. All 79 patients were dead at last follow-up with a median survival of 14 months, with few survivals > 5 years. Only operable vs. inoperable tumor was a statistically favorable factor in univariate analysis (p<0.01). In multivariate analysis, mitotic rate > 50/5 mm2 was significant for a shorter survival (HR 5.25, 95% CI 1.65-16.8., p<0.01). Histologic and clinicopathologic similarity of extragastrointestinal retroperitoneal GISTs with GISTs of GI-tract suggests their GI tract origin. Potentially overlapping features between GIST and other retroperitoneal tumors necessitate use of multiple diagnostic markers and molecular genetic studies.