BACKGROUND: Early prediction and management are crucial for treating breast cancer-related lymphedema (BCRL), yet the risk factors remain poorly understood. This study aims to explore the relationship between postoperative changes in serum cholesterol levels and the development of lymphedema. METHODS: This retrospective study analyzed breast cancer patients who underwent surgery between March 2014 and March 2019. We assessed the development of lymphedema and changes in high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), and total cholesterol (TC) levels. Preoperative values were compared with those measured within 6 months post-surgery, and logistic regression models were used for statistical analysis. RESULTS: Among the 906 patients studied, 87 (9.6%) developed lymphedema, with a median onset of 15 months. An increase in serum HDL levels relative to baseline was associated with a reduced risk of lymphedema (odds ratio [OR] 0.94 per unit increase, 95% confidence interval [CI]: 0.92-0.95), even after adjusting for established factors such as body mass index, type of axillary surgery, number of lymph nodes removed, regional radiotherapy, and chemotherapy. In contrast, elevated serum TG levels were linked to a higher risk of lymphedema (OR 1.003 per unit increase, 95% CI: 1.001-1.006). No significant associations were found with changes in LDL or TC levels (p >
0.05). CONCLUSION: Postoperative changes in HDL and TG levels are significantly associated with the risk of developing lymphedema, suggesting their potential role as early indicators. These results have important clinical implications for guiding follow-up care and early intervention strategies, although further validation is needed.