Vemurafenib is a highly efficient BRAF inhibitor for metastatic melanoma patients carrying the V600 mutation: progression-free survival is prolonged to ∼6 months and 50–80% of the patients show objective tumor responses. S100B and lactate dehydrogenase (LDH) are established tumor markers in routine melanoma follow-up. This study evaluated their potential as response and progression markers during vemurafenib treatment. A cohort of 44 patients with stage IV melanoma disease who were treated with vemurafenib was retrospectively analyzed. Staging was performed every 6–8 weeks comprising computed tomography scans and measurement of LDH and S100B levels. Response Evaluation Criteria In Solid Tumors (RECIST) criteria were used for standardized radiological response evaluations. The correlation between response or progression and LDH and S100B levels was analyzed using accuracy tests, Spearman’s rank correlation ρ, and polynominal regression analyses. There was a good correlation between S100B and LDH decline and a RECIST-confirmed response, especially when S100B and/or LDH were elevated at baseline (accuracy, 81.2% for S100B and 85.7% for LDH). However, the accuracy in case of RECIST-confirmed progression and S100B/LDH levels was low – 30.3% for S100B and 32.4% for LDH. Neither Spearman’s rank correlation ρ nor polynomial regression analyses showed a correlation between the clinical course and S100B/LDH levels. Measurement of S100B and LDH levels during treatment with vemurafenib indicates an initial response; however, this does not seem to be sufficient in detecting tumor progression and is thus not an alternative to monitoring with imaging examinations.