Objective: To establish evidence and standards for syndrome differentiation of patients with chronic skin ulcer of lower limbs, which can be used to supervise and further improve the clinical treatment. The evidence and standards would also lay a foundation for the integrative evaluation system of clinical effects. Methods: This is a prospective study of clinical case collection and analysis. The syndrome factors of chronic skin ulcer of lower limbs were collected from clinical cases, and then the essential factors of syndromes were chosen to make cluster analysis and principal component analysis. After syndrome classification, specialist consultation was performed. Forecasting syndrome models were established on the basis of the statistical analysis and the specialist consultation. Results: The syndrome factors in 338 cases of chronic skin ulcer of lower limbs were clustered into four syndrome categories including deficiency of both qi and blood, spleen deficiency with dampness encumbrance, qi deficiency with blood stasis and blood stagnation with dampness-heat. The deficiency of both qi and blood, and qi deficiency with blood stasis were merged into qi deficiency with blood stasis by expert revision. The primary and secondary symptoms were identified by principal component analysis and average ranking determined by experts. The qi deficiency with blood stasis, spleen deficiency with dampness encumbrance, and blood stagnation with dampness-heat could reflect the clinical syndrome characteristics in patients with chronic skin ulcer of lower limbs. Conclusion: Chronic skin ulcer of lower limbs can be differentiated in three syndrome types, and differentiation of local symptoms of the ulcer is very important in syndrome differentiation of chronic skin ulcer of lower limbs.