Keratoacanthoma (KA) is a benign keratinocytic neoplasm that spontaneously regresses after 3-6 months and shares features with squamous cell carcinomas (SCCs). Furthermore, there are reports of KAs that have metastasized, invoking the question of whether KA is a variant of SCC (Hodak et al., 1993). To date, no reported criteria are sensitive enough to discriminate reliably between KA and SCC, and consequently there is a clinical need for discriminating markers. Our previous study analyzed 132 KAs and 29 SCCs and revealed significantly different regions of genomic aberrations using chromosomal comparative genomic hybridization (CGH). In the present study, we applied array CGH to investigate 98 KAs and 22 SCCs from the above samples. The result shows that all KAs and SCCs have some degree of genetic aberrations. The distribution of numbers of aberrant clones per sample differed significantly between KAs and SCCs (P<0.02), which also demonstrated recurrent aberrations that differed significantly (P<0.001), as illustrated by unsupervised cluster analysis. Classifiers for clinicopathological parameters of KAs were established based on t-test statistics and permutation tests. Tumor size, fibrosis, and inflammation, which are related to the developmental stages of KAs, showed significant (t-test, permutation test) associations with aberrations of selected genomic regions. This suggests chromosomal instability during the whole life cycle of KAs.