Interferon (IFN)-dependent cellular effects are mediated by transcriptional induction of responsive genes, collectively referred to as IFN-stimulated genes (ISGs). Which ISGs regulate the potent antiviral, antiproliferative, apoptosis-inducing, antiangiogenic, and immunologic effects of IFNs remains largely undetermined. To identify genes that might be useful for predicting or targeting apoptosis induction in response to IFNs, WM9 melanoma cells were assessed. WM9 cells had equivalent antiviral activity in response to IFN-beta and IFN-alpha2 but underwent apoptosis only in response to IFN-beta. RNA samples from WM9 cells and WM35 cells, a second melanoma cell line, treated with IFN-alpha2 or IFN-beta were assessed on oligonucleotide arrays. For 95% of genes assessed, IFN-beta was more potent than IFN-alpha2 in inducing ISG expression. Using a 22,000-gene oligonucleotide array, the largest yet reported for assessing ISG induction, approximately 910 genes were identified as induced by IFN-beta at 500 U/ml, and 260 ISGs were identified as significantly induced by IFN-beta at both 50 and 500 U/ml. Of these 260, 209 were defined as new ISGs based on the array analysis. Confirmation by Northern blot or semiquantitative or quantitative PCR was undertaken for 28, and all were confirmed. Nearly half of the 260 genes were functionally categorized as encoding growth-regulatory proteins. Of the 104 with described growth-regulatory function, 71 were induced more than three times by 500 U/ml and twice by 50 U/ml IFN-beta, and 48 of these were new ISGs. Included in this latter category were tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), XIAP-associated factor 1 (XAF1), galectin 9, a cyclin E binding protein, amphiphysin 1, MyD88, and several ubiquitin pathway genes. The diversity of stimulated genes suggests the full therapeutic potential of IFN regulation of gene expression has yet to be realized.