Background: Congenital vascular malformations (CVMs) are vascular lesions that result from developmental errors during embryogenesis. They can occur anywhere in the body, causing pain, bleeding, ulcers, disfiguration, organ failure or limb loss. Depending on intralesional blood flow dynamics, CVMs can be broadly classified into low-flow (LF), which involve veins, lymphatics, capillaries or a mixture, and high-flow (HF), which involve arteries and veins. Accurate diagnosis and monitoring of LF and HF CVMs remains challenging and requires a wide range of imaging modalities. Aim: We sought to identify potential diagnostic serum biomarkers, particularly those pertaining to the processes of inflammation and angiogenesis. Methods: Sera were isolated from the peripheral bloods of consented healthy controls ( n = 10) and patients diagnosed as having either LF ( n = 10) or HF ( n = 10) CVMs. Various mediators of inflammation and angiogenesis were analysed in the sera using the Inflammation 20-Plex and Angiogenesis 18-Plex Human ProcartaPlex™ Panels. The levels of these mediators in patients with LF or HF CVMs were compared with those in healthy controls using the Kruskall-Wallis test and correlated with lesion volumes and visual analogue scores for pain using the Spearman rank correlation test. Results: Compared to healthy controls, the inflammatory mediators E-selectin, IFNα, IFNγ, IL1β, IL4, IL12, IL17, MIP1α, MIP1β and TNFα were elevated in the sera of LF CVM patients, whereas only MIP1α was raised in the sera of HF CVM patients. None of the angiogenic mediators were altered in the sera of patients with LF or HF CVMs. Serum IFNα, IFNγ, IL4, IL12, TNFα, VEGFA, VEGFD and syndecan correlated positively with pain scores in patients with LF CVMs, whereas only IP10 did in patients with HF CVMs. Serum Ang1 and leptin correlated negatively with lesion volumes in patients with LF or HF CVMs, respectively. Conclusion: Serum inflammatory mediators could be used as biomarkers to distinguish LF from HF CVMs and their expression seemed to be associated with pain severity in patients with LF CVMs. The angiogenic mediators Ang1 and leptin were associated with lesion volumes in patients with LF or HF CVMs, respectively.