BACKGROUND AND PURPOSE: Attributing to their anti-proliferative effect, both rapamycin and PPAR could halt the progression of ADPKD. Whether combined use can enhance effect is unknown. EXPERIMENTAL APPROACH: The present study used rapamycin and the PPAR agonist rosiglitazone concomitantly to observe their effects on the proliferation of ADPKD cyst-lining epithelial cells and the progression of ADPKD in Han:SPRD rats. KEY RESULTS: Concomitant use of the two drugs inhibited the proliferation of WT9-12 cells significantly through a superimposition effect. Rosiglitazone inhibited the phosphorylation of mTOR target p70S6K. Concomitant use of rosiglitazone and rapamycin further down-regulated the p-p70S6K level. Rosiglitazone also inhibited the phosphorylation of Akt and antagonize the activation of Akt induced by rapamycin. Concomitant use of rosiglitazone and rapamycin significantly retarded the deterioration of renal function, decreased cyst cell proliferation and interstitial fibrosis in Han: SPRD rats. Rapamycin significantly increased cholesterol levels in the blood, whereas rosiglitazone mitigated rapamycin-induced hyperlipidemia. CONCLUSION AND IMPLICATIONS: These results indicate that the effects of concomitant use of rosiglitazone and rapamycin in inhibiting the proliferation of WT9-12 cells and delaying the progression of ADPKD in Han:SPRD rats are stronger than those of either drug alone. The present study may provide a new strategy for the long-term treatment of ADPKD.