We studied differential global gene expression in four melanoma cell lines with three cell lines without homozygous deletion of the CDKN2A locus using HG-U133A microarrays with 22 277 transcripts. None of the cell lines carried mutations in the B-RAF and N-RAS genes. Data analysis using stringent criteria showed specific upregulation of 70 genes and downregulation of 86 genes in cell lines with homozygous deletion of the CDKN2A gene. A comparison with previous expression data showed overlapping of upregulation and downregulation of seven and 23 genes, respectively, in melanoma cell lines with homozygous deletion of the CDKN2A locus or mutations in the B-RAF and N-RAS genes. Microarray data for eight selected genes were validated with an extended number of cell lines using quantitative real-time polymerase chain reaction. The upregulated genes in cell lines with the deletion besides others included MAGE A2 [fold change 128, 95% confidence interval (CI) 82.8–172.2; t-test P=0.004], MAGE A6 (fold change 623, 95% CI 473.4–772.1; t-test P=0.001), MAGE A12 (fold change 90, 95% CI 65.1–115.5; t-test P=0.001) and dopachrome tautomerase (fold change 42, 95% CI 32.5–51.8; t-test P=0.001). Downregulated genes included interleukin 18 (fold change 489, 95% CI 146.4–831.2; t-test P=0.04), ID2 (fold change 3, 95% CI 2.2–4.9; t-test P=0.001), KLF4 (fold change 9, 95% CI 4.3–14.7; P=0.01) and CD24 antigen (fold change 1308, 95% CI 766.0–1850.8; t-test P=0.01). The upregulated genes common to cell lines with homozygous deletion of the CDKN2A gene and mutations in B-RAF and N-RAS gene included those that are involved in RAS/RAF/MEK/ERK pathways. Our results highlight effects of homozygous deletion of the CDKN2A locus on global gene expression.