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Simple Summary: Primary cutaneous melanoma (PCM) is a highly aggressive and potentially lethal form of skin neoplasm with a rapidly increasing incidence rate worldwide. The most common genetic aberration in PCM is the BRAF gene p.V600E pathogenic variant. The use of liquid biopsy (LB), which is a non-invasive, low-risk procedure that can be repeated multiple times, is becoming increasingly important in precision oncology. Because of the limited information about the applicability of LB in melanoma, here we investigate the correlation analyses and statistical significance between histopathological staging and molecular alterations in tumor-derived and cell-free DNA. The Breslow depth (BD) and Clark level were applied to categorize the study population. A positive correlation was proven between the tumor depth and peripheral blood plasma cfDNA yield in all mutant and negative cases. This observation is also supported by the fact that a statistically significantly higher concentration of cfDNA can be isolated from Clark V category cases compared to the others. Here, we investigate the correlation and statistical analyses between histological staging and molecular alterations in tumor-derived (tdDNA) and cell-free DNA (cfDNA) obtained from early-stage primary cutaneous melanoma (PCM) patients using digital PCR (dPCR) for the detection of the BRAF p.V600E somatic pathogenic variant. In the prospective study, a total of 68 plasma and paired tdDNA samples, and in the retrospective cohort, a total of 100 tdDNA samples were analyzed using dPCR and reverse hybridization StripAssay. The Breslow depth (BD) and Clark level were applied to categorize the study population. Our results demonstrate that dPCR is a highly sensitive and specific method for the detection of BRAF p.V600E somatic variants in cfDNA samples from PCM patients. A strong correlation was detected between BD and cfDNA concentration in all mutant and negative cases, between the tdDNA concentration and the tumor-derived variant allele frequency (VAF) of BRAF p.V600E, between the tdVAF and the cfVAF in all cases, and between the cfDNA and cfVAF in mutant cases. The tdVAF and cfVAF of BRAF p.V600E and cfDNA concentration were the highest in Clark's V category. The cfDNA concentration was statistically significantly higher in Clark's III, IV, and V groups compared to cases with a better prognosis. It can also be explained by the fact that cases with a more advanced stage classification release more cfDNA into the peripheral circulation. [ABSTRACT FROM AUTHOR]