Background: Recurrent aphthous ulcers (RAU) are common painful inflammatory lesions of the mucous lining of the mouth. Endocan, previously identified as endothelial cell specific molecule-1, is implicated as a vital player in the regulation of several inflammatory processes. A number of inflammatory cytokines and pro-angiogenic growth factors including VEGF upregulate endothelial cells synthesis and expression of endocan. Material and Methods: Clinical scores of pain and ulcer size as well as level of endocan and VEGF were determined in swaps from aphthous ulcer and contra lateral normal mucosa in 30 patients (nine males and twenty one females) with age ranging from 18 to 45 years and mean age is 31.5 years. Results: In the early days of ulcer development, ulcer showed statistically significantly higher mean endocan (8.2 ±5.3) and VEGF levels (1220.7 ±294.6) than control healthy mucosal site (1.1 ±0.5) and (518.6 ± 61.7) respectively. An increase in endocan is associated with an increase in pain score and vice versa. A statistically significant positive correlation were also found between endocan and VEGF levels. Conclusions: Endocan and VEGF are strongly associated with the destructive phase of minor aphthous ulcers especially Endocan which was positively correlated with pain severity