Abstract: Objective To investigate the clinical efficacy and safety of tacrolimus combined with low-dose sirolimus for pediatric steroid-resistant nephrotic syndrome. Methods Children with steroid-resistant nephrotic syndrome diagnosed in our hospital from October 2013 to October 2016 were included in the study. The inclusion criteria met the diagnostic criteria formulated by the Nephrology Group of the Society of Pediatrics, Chinese Medical Association in 2001. They were randomly divided into group A (27 cases) and group B(27 cases) using a random number table. Group A was treated with tacrolimus + low dose glucocorticoid; group B was treated with tacrolimus + low-dose sirolimus + low-dose glucocorticoid tacrolimus. The changes of interleukin-2, interleukin-13, interferon-gamma (INF-γ), blood routine test results, liver and kidney function test results, blood lipid, 24-hour urinary protein, blood sugar, blood-drug concentration and other biochemical indicators were compared, and the clinical efficacy and adverse reactions were analyzed. Results The total cholesterol, serum creatinine, glomerular filtration rate, albumin and 24-hour urinary protein in the two groups were significantly improved at 3 months and 6 months after treatment (P<0.05). Compared with group A, the total cholesterol, serum creatinine, glomerular filtration rate, albumin and 24-hour urinary protein in group B were significantly improved at 3 months and 6 months after treatment. (P<0.05). After treatment, the levels of IL-2 and INF-gamma in two groups were significantly lower than those before treatment, while the levels of IL-13 were significantly higher, with difference of statistical significance (P<0.05); compared with group A, the levels of IL-2 and INF-gamma in group B were significantly lower than those in group A at 3 months and 6 months after treatment, while the levels of IL-13 were significantly higher than those in group A, with difference of statistical significance (P<0.05). After treatment, the blood concentration of tacrolimus in group B was slightly lower than that in group A, with difference of statistical significance (P<0.05); although the total remission rate in group B was slightly higher than that in group A, there was no statistically significant difference (P>0.05). The incidence of adverse reactions and recurrence rates in group B were significantly lower than those in group A, with difference of statistical significance (P<0.05). Conclusions The triplet regime of tacrolimus + low dose glucocorticoid combined with low-dose sirolimus has higher safety and effectiveness than tacrolimus alone, which can better improve biochemical indicators such as cholesterol, serum creatinine, glomerular filtration rate, albumin and 24-hour urinary protein, and reduce occurrence of recurrence and adverse reactions.