Expression of adenosine deaminase acting on RNA1 (ADAR1) is driven by alternative promoters. Promoter P_A, activated by interferon (IFN), produces transcripts that encode the inducible p150 ADAR1 protein, whereas P_B specifies the constitutively expressed p110 protein. We show using Stat1^−/−, Stat2^−/− and IRF9^−/− MEFs that induction of ADAR1 p150 occurs by STAT2- and IRF9-dependent signaling that is enhanced by, but not obligatorily dependent upon, STAT1. Chromatin immunoprecipitation analysis demonstrated STAT2 at the P_A promoter in IFN-treated Stat1^−/− cells, whereas IFN-treated wild-type cells showed both STAT1 and STAT2 bound at P_A. By contrast, with human 2fTGH cells and mutants U3A or U6A, ADAR1 induction by IFN was dependent upon both STAT1 and STAT2. These results suggest that transcriptional activation of Adar1 by IFN occurs in the absence of STAT1 by a non-canonical STAT2-dependent pathway in mouse but not human cells.