Lymphedema is a chronic condition that can follow cancer treatment, and liposuction has been shown to be an effective approach for reducing limb volume in advanced cases. However, recurrence rates vary widely, with prior erysipelas identified as a potentially significant factor influencing prognosis. This study aimed to identify key risk factors for recurrence following liposuction in patients with cancer-associated secondary lymphedema, develop a predictive nomogram model, and investigate the molecular mechanisms by which previous erysipelas may affect recurrence. In a retrospective analysis of 1,016 patients, multivariate logistic regression and propensity score matching identified four independent risk factors, namely, prior erysipelas, hyperlipidemia, severe distal limb edema, and older age, with erysipelas showing the strongest association with poor outcomes (OR 3.98; 95% CI: 2.81-5.69). A validated nomogram demonstrated high predictive accuracy (C-index 0.757, Brier score 0.176) and net clinical benefit in estimating recurrence risk. The nomogram supports personalized treatment strategies, potentially improving patient outcomes. Transcriptome sequencing further revealed that previous erysipelas exacerbates lymphedema through inflammation, tissue remodeling, and metabolic dysregulation, suggesting potential therapeutic targets.