Although integrin β 3 is known to play an important role in melanoma progression and invasion, regulation of integrin β 3 expression in melanoma has not been analysed in detail until today. As transcriptional regulation of integrin β 3 was ruled out by our analysis, we concentrated on the regulation by microRNAs (miRNAs). Comparing primary melanocytes and malignant melanoma cell lines, we found that one candidate miRNA, miR-let-7a, was lost in melanoma and sequence analysis suggested an interaction with the 3′-untranslated region (3′-UTR) of integrin β 3 mRNA. Transfection of melanoma cells with let-7a pre-miR TM molecules resulted in the downregulation of integrin β 3 mRNA and protein expression. In addition, we cloned the 3′-UTR of the integrin β 3 mRNA containing the let-7a target sequence into a reporter plasmid and revealed that let-7a negatively regulates reporter gene expression. The repressed expression of integrin β 3 accompanies with reduced invasive potential of melanoma cells transfected with synthetic let-7a molecules observed in Boyden chamber assays. On the other hand, the induction of integrin β 3 expression was achieved in melanocytes by transfection with let-7a anti-miRs, resulting in invasive behavior of transfected melanocytes. In summary, we determined miRNA let-7a to be an important regulator of integrin β 3 expression and showed that the loss of let-7a expression is involved in development and progression of malignant melanoma.