Desmoplastic reaction of the mesentery is commonly seen in patients with neuroendocrine tumors of the small intestine. However, it is not clear whether desmoplastic reaction is associated with tumor-specific characteristics and diminished prognosis. Therefore, the aim of this study was to investigate whether the presence of a desmoplastic reaction correlates with prognostic and molecular markers of neuroendocrine tumors of the small intestine. Patients with neuroendocrine tumors of the small intestine operated at our department from 2000 to 2016 were analyzed. Patient and tumor characteristics were evaluated. Kaplan-Meier and multivariate analyses were performed. In total, 148 patients underwent surgery, and preoperative imaging was available in 113 patients. A total of 45 patients showed desmoplastic reaction of the mesentery and progression-free survival was significantly impaired (26 months versus 65.4 months) compared with patients without desmoplastic reaction. These patients had significantly more often distant metastases (84.4% vs 39.7%), lymphatic vessel (68.9% vs 44.1%), and perineural tissue infiltration (57.8% vs 17.6%) compared with patients without desmoplastic reaction. However, proliferation index (positive desmoplastic reaction 4.1% versus negative desmoplastic reaction 3.3%) and tumor size (positive desmoplastic reaction 2 cm versus negative desmoplastic reaction 1.9 cm) were not diverging significantly. This study revealed that tumors leading to desmoplastic reaction are more aggressive, despite similar Ki67 indices.