Nephrolithiasis is a very common disease in which cell-crystal adhesion is an essential mechanism for kidney stone formation. This study has explored the anti-adhesion function of the microRNA, miR-34a, by targeting CD44, a cell surface receptor, in human renal epithelial (HK-2) cells. The expression of CD44 was monitored by qPCR and western blot. A luciferase assay validated the target of miR-34a in CD44 3 ' UTR. Immunofluorescence staining under confocal microscopy was used to detect the cell-crystal adhesion effects in vitro. Pizzolato staining was performed to examine the adhesion role of miR-34a in vivo. In HK-2 cells, miR-34a was down-regulated and CD44 was up-regulated when exposed to calcium oxalate monohydrate crystals. Moreover, miR-34a negatively regulated the expression of CD44. According to the luciferase report assay, miR-34a direct targeted a binding site in the CD44 3 ' UTR. In vitro experiments, miR-34a overexpression inhibited CD44 expression and cell-crystals adhesion; whereas CD44 overexpression showed reversed results. Furthermore, miR-34a suppressed cell-crystals adhesion and stone formation in vivo. These findings indicate that miR-34a targets CD44 in HK-2 cells and inhibits cell-crystal adhesion both in vitro and in vivo. Based on these results, miR-34a may be a potential therapeutic target for renal stone disease.