Background Angiogenesis underpins tumor growth, survival, and metastasis in many solid cancers, including malignant melanoma. One way to quantify tumor angiogenesis is to assess microvessel density (MVD) using endothelial immunohistochemical markers. In routine practice, anti-factor VIII-related antigen, anti-CD31, and anti-CD34 are all used for this purpose, but how they stack up against each other in cutaneous melanoma is still not very clear. We compared these three markers to determine which is the most useful for MVD evaluation in this specific context. Methods We conducted an analytical comparative study using archival cutaneous melanoma samples collected between 2015 and 2021 at the University of Pretoria. Immunohistochemistry with anti-factor VIII, anti-CD31, and anti-CD34 antibodies was performed on 102 tissue sections from 34 cases. Three pathologists independently counted the microvessels in 10 high-power fields (200× magnification) for each marker. Data were analyzed using repeated-measures ANOVA with post-hoc testing (p<0.05). Results The mean MVDs were 77.33 (±29.57) for anti-CD34, 61.67 (±34.85) for anti-CD31, and 58.67 (±23.51) for anti-factor VIII. Anti-CD34 highlighted significantly more microvessels than anti-CD31 or anti-factor VIII (p=0.003). Post-hoc analysis confirmed significant differences between CD31 and CD34, and between CD34 and factor VIII (p=0.001). In contrast, anti-CD31 and anti-factor VIII did not show a meaningful difference in sensitivity or specificity for microvessel detection. Conclusion In this series, anti-CD34 performed better than anti-CD31 and anti-factor VIII in highlighting MVD in cutaneous melanoma. This is in line with reports from other solid tumors, suggesting that CD34 tends to pick up more vessels. While our sample size is modest and drawn from a single center, the data support the use of anti-CD34 as the preferred marker for intratumoral MVD assessment in surgical pathology, ideally alongside clinicopathological correlation and, where needed, complementary markers.