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The interferon receptors of C3H/10T½ mouse cells respond differently to α and β interferons under certain conditions. If C3H/10T½ cells which have been maintained in logarithmic growth phase are exposed to trypsin or Pronase immediately before they are treated with mouse interferons, they evince an antiviral response to α interferon but not to β interferon. In contrast, contact-inhibited C3H/10T½ cells, L-929 mouse cells or human HEL cells lost the ability to respond to both α and β interferons after treatment with trypsin or Pronase. When L-929 cells are incubated at 37 °C following exposure to these proteolytic enzymes, they completely regain their ability to respond to mouse β interferon within 2 h. These observations suggest that the receptors for α and β interferons are different in their topographical distribution in C3H/10T½ cells.