Objective To observe the therapeutic effect of a small dose of sirolimus-based quadruple immunosuppressive regimen for the treatment of renal allograft dysfunction. Methods Totally 59 patients (44 males and 15 females) with renal allograft dysfunction treated with triple immunosuppressants (mycophenolic acid/mizoribine+calcineurin inhibitors[CNIs]+glucocorticoids) were selected. While the dose of CNIs was reduced, a small dose of sirolimus (initial dose 0.5 mg/d, target blood concentration 2-4 ng/mL) was added so as to convert to the quadruple immunosuppressive regimen. The changes of the blood concentrations of sirolimus and CNIs were recorded, and the indexes of the serum creatinine and blood lipid were analyzed before and after conversion. Results All the 59 patients completed the conversion of quadruple therapy, and the blood concentration of sirolimus was (4.74±1.62) ng/mL; and the blood concentration of CNIs was decreased by (37.00±19.00)% in 53 cases. After adjustment of treatment, serum creatinine level was significantly decreased ([111.53±24.87] μmol/L vs[148.88±27.64] μmol/L, P<0.01). No significant changes were found for the triglyceride ([1.93±1.08] mmol/L vs[1.89±0.77] mmol/L, P>0.05) or cholesterol ([5.30±1.39] mmol/L vs[4.96±1.19] mmol/L, P>0.05). The 59 patients were divided into early conversion group (conversion to quadruple therapy within 1-23 months after renal transplantation, n=44) and late conversion group (conversion to quadruple therapy within 32-159 months after operation, n=15). The proportion of patients with normal renal function in the early conversion group was significantly higher than that in the late conversion group (77.27%[34/44] vs 40.00%[6/15], P<0.05); and the serum creatinine level in the early conversion group was significantly lower than that before conversion ([106.41±19.78] μmol/L vs[151.43±28.68] μmol/L, P<0.05), while no significant decrease was noticed in the late conversion group ([126.53±32.18] μmol/L vs[141.40±24.76] μmol/L, P>0.05). Conclusion Reducing CNIs, while adding a small dose of sirolimus, can significantly improve renal allograft dysfunction after renal transplantation, without increasing the adverse reactions of dyslipidemia. A small dose of sirolimus-based quadruple immunosuppressive therapy is more effective in patients with early postoperative renal allograft dysfunction.