This dataset was acquired to identify human proteins binding to tetraphosphate mRNA cap analogs. Affinity resins were derivatized with tetraphosphate mRNA cap analogs or a trinucleotide cap control and affinity purification performed in HEK293F cell extracts. The pulled-down proteins were eluted using soluble cap analogs, subjected to digestion with trypsin, TMT labelling, and nLC-MS/MS analysis.