Solid pseudopapillary neoplasm (SPN) is a pancreatic tumor, which should be distinguished from neuroendocrine tumors (NET). It was postulated that SPN arise from the neural crest (NC). The purpose of the study was to examine expression levels of NC markers: L1 cell adhesion molecule (L1CAM) and nerve growth factor receptor (NGFR) in SPN and NET using immunohistochemistry (IHC) and tissue microarrays, aiming to test their potential utility as auxiliary IHC markers for differential diagnosis of SPN vs. NET. In the training cohort (n = 16 SPN), all cases showed L1CAM expression (usually weak, median extent 45% of cells), and NGFR expression (usually moderate to strong, median extent 100% of cells). In the validation cohort (n = 10 SPN), 90% of cases were L1CAM-positive (usually weak expression, median extent 15% of cells), and 100% were NGFR-positive (usually weak expression, median extent 70% of cells). Among NET cases (n = 29) L1CAM was found in 2 (7%), and NGFR in 1 case (3%). L1CAM and NGFR were expressed in SPN, but the intensities and extent of IHC staining differed across the cases. L1CAM and NGFR expression was rare in NET. Both markers may be further tested for their diagnostic utility for SPN vs. NET differential diagnosis. L1CAM/NGFR expression supports NC origin/differentiation of SPN.