Incorporation of selenocysteine (Sec) into selenoproteins (SPs) occurs in response to UGA that is recoded from its normal termination function. This process requires a specific structure in the 3′‐UTR of SP mRNAs, a SECIS element. We previously found that UGA codes for both Sec and Cys in Euplotes crassus and that Sec insertion is dependent on the position of UGA within the ORF. Herein, we report that the position of UGA within human TR1 (hTR1) mRNA is also important for efficient Sec insertion. Conversely, Sec was inserted at any placement of UGA within hTR3. Replacement of the 3′‐UTR of hTR3 with the corresponding segment of Euplotes TR2 restricted Sec insertion at the C‐terminal protein portion, similar to Sec insertion in Euplotes. Replacement of the 3′‐UTR of Euplotes TR2 with the 3′‐UTR from hTR3 changed the UGA coding function of eTR2, leading to insertion of Sec at previously restricted positions. Similar results were observed when only the SECIS elements were switched preserving the rest of the 3′‐UTRs. Mutations in hTR3 SECIS changed the UGA coding function, whereas mutations in the 3′‐UTR had little or no effect. The data indicate a key role of SECIS in UGA position‐dependent Sec insertion into mammalian SPs.