Progression of prion diseases is driven by the accumulation of prions in the brain. Ablation of microglia or deletion of the eat-me-signal, milk-fat globule epidermal growth factor VIII (Mfge8), accelerates prion pathogenesis, suggesting that microglia defend the brain by phagocytosing prions. Similar to Mfge8, developmental endothelial locus–1 (Del-1) is a secreted protein that acts as an opsonin bridging phagocytes and apoptotic cells to facilitate phagocytosis. We therefore asked whether Del-1 might play a role in controlling prion pathogenesis. We assessed the anti-inflammatory and phagocytosis-promoting functions of Del-1 in prion disease and determined whether Del-1 complements Mfge8 in prion clearance in mice with a C57BL/6J genetic background. We found that Del-1 deficiency did not change prion disease progression or lesion patterns. In addition, prion clearance and scrapie prion protein deposition were unaltered in Del-1–deficient mice. In addition, prion-induced neuroinflammation was not affected by Del-1 deficiency. We conclude that Del-1 is not a major determinant of prion pathogenesis in this context.