Background/Aims: Connective tissue growth factor (CTGF) is a pro-fibrotic growth factor that acts downstream of transforming growth factor (TGF)-β. However, CTGF regulation remains unknown. We tried to determine the effect of two commonly used immunosuppressants, cyclosporine (CsA) and sirolimus (SRL), on CTGF expression in a model of chronic nephrotoxicity. Methods: Adult Sprague-Dawley rats kept on a low-salt diet were treated daily for 4 weeks with vehicle (VH), SRL (0.3 mg/kg), CsA5 (5 mg/kg), CsA10 (10 mg/kg) or both CsA5 and SRL. CTGF and TGF-β<sub>1</sub> expressions were evaluated by Northern blot. Functional and histologic parameters in addition to number of apoptotic cells were determined. Results: At 28 days, both CsA doses were capable of inhibiting CTGF mRNA expression to levels similar to control. On the other hand, SRL increased CTGF expression by 3.5-fold. However, addition of CsA to SRL completely reversed that trend and returned levels to control. The results were different for TGF-β<sub>1</sub>, which was increased by both CsA and SRL and to a greater extent by the drug combination. Conclusion: Unlike TGF-β, CTGF does not seem to play an important role in CsA-induced chronic nephrotoxicity. In addition, calcineurin-dependent pathways are likely involved in CTGF regulation.