Heterogeneous neointimal response has been observed after implantation of all generations of coronary stents. Our aim was assessing local factors of shear stress (SS) and plaque characteristics in neointimal response after implantation of bioresorbable scaffolds (BRS) in bifurcations. Ten patients from the BIFSORB pilot study were analysed. Follow-up optical frequency domain imaging (OFDI) was performed at 1 month and 2 years. Coronary lumen and BRS structure were reconstructed by fusion of OFDI and angiography and were used for subsequent flow simulation. Plaque arc degree and SS were quantified using post-procedural OFDI data and were matched with follow-up OFDI using anatomical landmarks. Strut-level and segment-level analysis were performed for 1-month and 2-year follow-up respectively. A total of 444 struts (54 jailing struts) were included at 1-month follow-up. Time-average SS (TASS) was significantly lower for covered struts than for uncovered struts in non-bifurcation segments (TASS: 1.81 ± 1.87 vs. 3.88 ± 3.72 Pa, p < 0.001). The trend remained the same for jailing struts, although statistically insignificant (TASS: 10.85 ± 13.12 vs. 13.64 ± 14.48 Pa, p = 0.328). For 2-year follow-up, a total of 66 sub-regions were analysed. Neointimal hyperplasia area (NTA) was negatively correlated with TASS in core-segments (ρ = − 0.389, p = 0.037) and positively correlated with plaque arc degree in non-core segments (ρ = 0.387, p = 0.018). Slightly stronger correlations with NTA were observed when combining TASS and plaque arc degree in both core segments (ρ = − 0.412, p = 0.026) and non-core segments (ρ = − 0.395, p = 0.015). Hemodynamic microenvironment and baseline plaque characteristics may regulate neointimal response after BRS implantation in bifurcation. These findings underline the combined role of plaque characteristics and local hemodynamics in vessel healing after stent implantation.