Background Since a non-negligible fraction of patients with metastatic melanoma does not experience long-term disease control, even with immunotherapy and targeted therapy, new biomarkers for patient stratification and treatment tailoring are needed in this setting. Objective We investigated the association of a novel immune-inflammatory blood-based biomarker, the Pan-Immune-Inflammation Value (PIV), with clinical outcomes of patients with metastatic melanoma receiving first-line therapy. Patients and Methods We retrospectively included patients treated at the Fondazione IRCCS Istituto Nazionale dei Tumori of Milan and having an available baseline complete blood cell count (CBC). PIV was calculated as: neutrophil count (10 3 /mm 3 ) × platelet count (10 3 /mm 3 ) × monocyte count (10 3 /mm 3 )/lymphocyte count (10 3 /mm 3 ). Results A total of 228 patients were included: 119 (52%) had been treated with immunotherapy and 109 (48%) with targeted therapy. PIV was significantly higher in patients with ECOG PS ≥ 1, high disease burden, synchronous metastases, and elevated baseline LDH level. High baseline PIV was independently associated with poor overall survival (adjusted hazard ratio HR: 2.06; 95% confidence interval CI: 1.30–3.29; adjusted P =  0.002) and progression-free survival (adjusted HR 1.56; 95% CI 1.01–2.41; adjusted P =  0.044). High PIV was also associated with primary resistance to both immunotherapy (odds ratio OR: 3.98; 95% CI 1.45–12.32; P =  0.005) and targeted therapy (OR: 8.42; 95% CI 2.50–34.5; P < 0.001). PIV showed a promising discrimination ability in terms of AIC and c-index when compared with other CBC-based biomarkers. Conclusions PIV may guide the treatment decision process and the development of novel first-line treatment strategies in melanoma, but warrants further study and validation.