Tetrafluorinated phenylalanines were incorporated into villin headpiece subdomain HP35, and their energetic contribution to protein stability was evaluated. In comparison to pentafluoro-phenylalanines, HP35 variants harboring tetrafluorinated phenylalanines exhibit increased thermal and thermodynamic stability by a large margin. The favorable stabilization is attributed to the electrostatic ArH center dot center dot center dot Pi interactions retained and strengthened by the highly, but not fully, fluorinated aromatic rings.