The utility of noble gases for phase determination has been limited by the lack of naturally occurring binding sites in proteins. Wild-type T4 lysozyme contains one such binding site. By mutating large hydrophobic residues to alanine, additional noble-gas binding sites have been successfully introduced into this protein. Using data from xenon derivatives of the wild type, two single mutants and the corresponding double mutant, experimental phases for T4 lysozyme have been determined using standard multiple isomorphous replacement (MIR) techniques. These phases, which were obtained from room-temperature data collected on a rotating-anode source, are comparable in quality with phases calculated using selenomethionine-based multiwavelength anomalous dispersion (MAD) methods on frozen crystals at a synchrotron. In addition, this method of introducing noble-gas binding sites near specific residues should provide useful information for determining the register of amino acids within electron-density maps and the positions of molecules within the unit cell.