Purpose: The role of inflammation in oxalate induced nephrolithiasis is debated. Our gene expression study indicated an increase in Interleukin-2 Receptor beta (IL-2Rβ) mRNA in response to oxalate. Herein, we evaluated IL-2Rβ expression and its down-stream signaling pathway in HK2 cells in an effort to understand the mechanisms of oxalate nephrotoxicity. Materials and Methods: HK-2 cells were exposed to oxalate for various time points in the presence or absence of SB203580, a specific p38 MAP kinase inhibitor. Gene expression data were analyzed by Ingenuity Pathway Analysis software. mRNA expression was quantitated via Real Time-PCR and changes in protein expression/kinase activation were analyzed by western blot. Results: Exposure of HK-2 cells to oxalate resulted in increased transcription of IL-2Rβ mRNA and increased protein levels. Oxalate treatment also activated IL-2Rβ signaling pathway (JAK1/STAT5 phosphoryylation). Moreover, the increase in IL-2Rβ protein was dependent upon p38-MAPK activity. Conclusions: These results suggest that oxalate-induced activation the IL-2Rβ pathway may lead to a plethora of cellular changes, the most common of which is the induction of inflammation. These results suggest a central role for p38-MAPK pathway in mediating the effects of oxalate in renal cells, and additional studies may provide the key to unlocking novel biochemical targets in stone disease.