Objective To investigate the effect of follistatin like protein 1(FSTL1) on oxidized low-density lipoprotein (Ox-LDL)-stimulated the phenotypic transformation of mouse vascular smooth muscle cell (VSMC). Methods Firstly, under Ox-LDL-stimulating, the expression of FSTL1 in VSMC was detected. Secondly, Western blotting was used to detect the signature proteins, α-smooth muscle actin(α-SMA) and osteopontin(OPN). Finally, the proliferation of VSMC was verified by proliferation experiments under the influence of Ox-LDL and FSTL1. Results Comparing to the normal group, the expression of FSTL1 was lower in the abnormal vessel regions, which was filled with Ox-LDL(0.223±0.010 vs. 0.097±0.019, P<0.01). VSMC was stimulated by Ox-LDL at 0, 12.5, 25 and 50 mg/L for 24 h respectively and the expression level of FSTL1 detected by Western blotting was 1.330±0.055, 0.905±0.027, 0.753±0.037 and 0.243±0.016 accordingly. It showed that the lowest expression level of FSTL1 was observed when Ox-LDL concentration increased to 50 mg/L (F=260.600, P<0.000 1). The expression of FSTL1 was 1.383±0.033, 0.782±0.047, 0.381±0.022 and 0.230±0.017 after 50 mg/L Ox-LDL stimulating VSMC for 0, 6, 12 and 24 h respectively, in which the expression of FSTL1 was the lowest when Ox-LDL induced 24 h(F=151.000, P<0.000 1). In addition, Ox-LDL stimulation reduced the expression of α-SMA(1.303±0.030 vs. 0.493±0.069, P<0.01) and SIRT1(0.993±0.044 vs. 0.613±0.030, P<0.01), while increasing the expression of OPN(1.001±0.031 vs. 2.698±0.001, P<0.01). However, the expression of OPN, α-SMA and SIRT1 showed opposite trend when VSMC was stimulated with both FSTL1 and Ox-LDL(OPN 2.698±0.002 vs. 1.590±0.001, P<0.05; α-SMA 0.493±0.062 vs. 0.653±0.015, P<0.05; SIRT1 0.613±0.030 vs. 1.231±0.011, P<0.05). Compared with Ox-LDL+FSTL1+DMSO group, VSMC in Ox-LDL+FSTL1+SIRT1 inhibitor group showed reduced α-SMA(0.530±0.033 vs. 0.283±0.032, P<0.01) and SIRT1(1.056±0.020 vs. 0.207±0.021, P<0.01), and increased OPN(1.643±0.047 vs. 3.533±0.100, P<0.01). The proliferation of VSMC was enhanced by Ox-LDL stimulation(0.870±0.010 vs. 1.890±0.020, P<0.01), while FSTL1 reduced this proliferation(1.890±0.021 vs. 1.200±0.023, P<0.05) via SIRT1(1.280±0.033 vs. 2.030±0.092, P<0.01). Conclusions Ox-LDL reduced the expression of FSTL1. FSTL1 could mitigate Ox-LDL-stimulated proliferation via SIRT1 effectively.