Abstract Background To investigate the association of tumor volumetric parameters in melanoma patients undergoing ¹⁸F-FDG-PET/CT with serologic tumor markers and inflammatory markers and the role as imaging predictors for overall survival. Methods A patient cohort with advanced melanoma undergoing ¹⁸F-FDG-PET/CT for planning metastasectomy between 04/2013 and 01/2015 was retrospectively included. The volumetric PET parameters whole-body MTV and whole-body TLG as well as the standard uptake value (SUV) peak were quantified using 50%-isocontour volumes of interests (VOIs) and then correlated with the serologic parameters lactate dehydrogenase (LDH), S-100 protein, c-reactive protein (CRP) and alkaline phosphatase (AP). PET parameters were dichotomized by their respective medians and correlated with overall survival (OS) after PET/CT. OS was compared between patients with or without metastases and increased or not-increased serologic parameters. Results One hundred seven patients (52 female; 65 ± 13.1yr.) were included. LDH was strongly associated with MTV (r_P = 0.73, p < 0.001) and TLG (r_P = 0.62, p < 0.001), and moderately associated with SUV_peak (r_P = 0.55, p < 0.001). S-100 protein showed a moderate association with MTV (r_P = 0.54, p < 0.001) and TLG (r_P = 0.48, p < 0.001) and a weak association with SUV_peak (r_P = 0.42, p < 0.001). A strong association was observed between CRP and MTV (r_P = 0.66, p < 0.001) and a moderate to weak association between CRP and TLG (r_P = 0.53, p < 0.001) and CRP and SUV_peak (r_P = 0.45, p < 0.001). For differentiation between patients with or without metastases, receiver operating characteristic (ROC) analysis revealed a cut-off value of 198 U/l for serum LDH (AUC 0.81, sensitivity 0.80, specificity 0.72). Multivariate analysis for OS revealed that both MTV and TLG were strong independent prognostic factors. TLG, MTV and SUV_peak above patient median were accompanied with significantly reduced estimated OS compared to the PET parameters below patient median (e.g. TLG: 37.1 ± 3.2 months vs. 55.9 ± 2.5 months, p < 0.001). Correspondingly, both elevated serum LDH and S-100 protein were accompanied with significantly reduced OS (36.5 ± 4.9 months and 37.9 ± 4.4 months) compared to normal serum LDH (49.2 ± 2.4 months, p = 0.01) and normal S-100 protein (49.0 ± 2.5 months, p = 0.01). Conclusions Tumor volumetric parameters in ¹⁸F-FDG-PET/CT serve as prognostic imaging biomarkers in patients with advanced melanoma which are associated with established serologic tumor markers and inflammatory markers.