In vitro, microRNA-126 (miR-126) inhibits SLK cell proliferation, inhibits the cell cycle, induces cell apoptosis, and reduces cell invasiveness. Double luciferase assays have shown that phosphatidylinositol-3 kinase (PI3K) is the miR-126 target in SLK cells. We aimed to investigate the influence of miR-126 on the phosphate and tension homology deleted on chromosome ten (PTEN)/PI3K/protein kinase B (AKT) pathway members in SLK cells and to determine the expression of these pathway members in Kaposi's sarcoma (KS). The mimic and inhibitor of miR-126 were transfected into SLK cells and PTEN and AKT1 expression was assayed in SLK cells by real-time quantitative PCR and western blotting. PTEN, AKT1, phosphorylated (P)-PTEN, and phosphorylated (P)-AKT expression in KS and paraneoplastic skin were assayed by immunohistochemistry. AKT1 expression was downregulated in SLK cells that overexpressed miR-126, while there was no significant difference in PTEN expression between SLK cells overexpressing miR-126 and those in which its expression was knocked down. PTEN and AKT1 were expressed in KS and paraneoplastic skin but P-AKT was not. Interestingly, P-PTEN was not expressed in paraneoplastic skin but it was expressed in 90% of KS biopsies (P < .05). P-PTEN expression was also significantly higher in visceral than in cutaneous KS (P = .01) and was higher in indoor than in outdoor workers (P = .018). In vitro, miR-126 negatively regulated AKT1 expression but no regulation of PTEN expression was evident. Results indicated that in KS, PTEN is activated and may therefore be a potential therapeutic target for KS. In addition, these results also indicate that sunlight may not be the cause of KS.