Prnp(-/-) mice lack the prion protein PrP(C) and are resistant to prion infections, but variable phenotypes have been reported in Prnp(-/-) mice and the physiological function of PrP(C) remains poorly understood. Here we examined a cell-autonomous phenotype, inhibition of macrophage phagocytosis of apoptotic cells, previously reported in Prnp(-/-) mice. Using formal genetic, genomic, and immunological analyses, we found that the regulation of phagocytosis previously ascribed to PrP(C) is instead controlled by a linked locus encoding the signal regulatory protein α (Sirpa). These findings indicate that control of phagocytosis was previously misattributed to the prion protein and illustrate the requirement for stringent approaches to eliminate confounding effects of flanking genes in studies modeling human disease in gene-targeted mice. The plethora of seemingly unrelated functions attributed to PrP(C) suggests that additional phenotypes reported in Prnp(-/-) mice may actually relate to Sirpa or other genetic confounders.