Selenoproteins are an essential and unique group of proteins in which selenocysteine (Sec) is incorporated in response to a stop codon (UGA). Reprograming of UGA for Sec insertion in eukaryotes requires a cis-acting stem loop structure in the 3' untranslated region of selenoprotein mRNA and several trans-acting factors. Together these factors are sufficient for Sec incorporation in vitro, but the process is highly inefficient. An additional challenge is the synthesis of Selenoprotein P (SELENOP), which uniquely contains multiple UGA codons. Full SELENOP expression requires processive Sec incorporation, the mechanism for which is not understood. In this study, we identify core coding region sequence determinants within the SELENOP mRNA that govern SELENOP synthesis. Using (75)Se labeling in cells, we determined that the N-terminal sequence (upstream of the 2nd UGA) and C-terminal sequence context are two independent determinants for efficient synthesis of full length SELENOP. In addition, the distance between the first UGA and the consensus signal peptide is also critical for efficiency.