Purpose: Effective predictors of the response to neoadjuvant chemotherapy (NAC) are still insufficient. This study aimed to investigate the predictive value of serum lipid profiles for the response to NAC in breast cancer patients. Methods: A total of 533 breast cancer patients who had received NAC were retrospectively studied. The pretreatment of serum lipids, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and lipoprotein-α, and clinicopathological characteristics were collected to assess their predictive roles. Results: Breast cancer patients had significantly lower TC, TG, HDL-C, and LDL-C levels than normal individuals. Among these indicators, TG and LDL-C levels and HDL-C level increased and decreased significantly after NAC, respectively. In estrogen receptor (ER)-positive patients, increased LDL-C level was associated with better outcomes. Moreover, the receiver operating characteristic curve analyses suggested that TG and HDL-C levels at diagnosis can be used as predictors of the response to NAC only in the ER-positive subgroup.According to univariate analyses, patients with low TG level (< 1.155 mmol/L) or high HDL-C level (≥ 1.305 mmol/L) in the ER-positive subgroup had more favorable clinical responses than the other patients in the subgroup. Furthermore, according to multivariate analyses, a high HDL-C level (≥ 1.305 mmol/L, p = 0.007) was an independent predictor of NAC efficacy. Conclusion High HDL-C level (≥ 1.305 mmol/L) before NAC and increased LDL-C level after NAC were associated with the better treatment response in ER-positive breast cancer patients.These results are potentially considered beneficial in establishing treatment decisions.