β 2 -microglobulin (β 2 m) is the smallest building block of molecules belonging to the immunoglobulin superfamily. By comparing thermodynamic and structural characteristics of chicken β 2 m with those of other species, we seek to elucidate whether it is possible to pinpoint features that set the avian protein apart from other β 2 m. The thermodynamic assays revealed that chicken β 2 m exhibits a lower melting temperature than human β 2 m, and the H/D exchange behavior observed by infrared spectroscopy indicates a more flexible structure of the former protein. To understand these differences at a molecular level, we determined the structure of free chicken β 2 m by X-ray crystallography to a resolution of 2.0Å. Our comparisons indicate that certain biophysical characteristics of the chicken protein, particularly its conformational flexibility, diverge considerably from those of the other β 2 m analyzed, although basic structural features have been retained through evolution.