Background: Outcomes of patients affected by advanced neuroendocrine carcinomas (NEC) with Ki-67 labeling index > 55% are heterogeneous regardless of the primary tumor site. We explored baseline inflammatory indexes and serum albumin levels to identify markers of response to standard first line chemotherapy. Methods: We retrospectively identified patients with advanced NEC treated with cisplatin (CP) or carboplatin (CB) and etoposide between 2015 and 2019 at the National Cancer Institute of Milan. Linear and Cox regressions were used to investigate, respectively, numeric and time-to-event outcomes. Maximization of log-rank statistics was used for optimal cutoffs finding. An artificial intelligence algorithm, random forest, was used to rank the impact of different clinical features on OS and PFS. Results: A total of 81 consecutive patients with different primary tumors (53 small cell lung carcinoma, 12 large cell neuroendocrine carcinoma, 10 gastrointestinal neuroendocrine carcinoma and 6 Merkel cell carcinoma) either treated with CP (n = 39) or CB (n = 42) were analyzed. Overall response rate (ORR), median progression free survival (PFS) and median overall survival (OS) were, respectively, 50.6%, 5.5 months (m) and 9.1m. Considered together, high serum albumin (SA > 3.5 g/dl) and low neutrophile-to-lymphocyte ratio (NLR < 3.59) identified a group of patients (n = 42) with longer median PFS and OS compared to the rest of the cohort (8.3m vs 1.5m, HR 3.58, CI 2.14-6.02, p< 0.001 for PFS and 12.6m vs 4.4m, HR 3.11, CI 1.88-5.18, p< 0.001 for OS); within this group a higher ORR (74% vs 36%, OR 5.01, CI 1.83-14.64, p = 0.002) was observed. Two multivariate models showed statistically significant associations of SA and NLR with PFS (p = 0.017 and p = 0.005) and OS (p = 0.016 and p = 0.036), independent of baseline ECOG performance status, age, sex, body mass index, smoking status, stage, hepatic tumor burden, primary site, histology, lactate dehydrogenase (LDH) serum levels, type of platinating agent and number of cycles. Two random forest models ranked SA, NLR and LDH as the most important factors for PFS and OS prediction. Conclusions: In the setting of advanced NEC with Ki-67 > 55% the combined use of SA and NLR identified two groups of patients with remarkably different outcomes, suggesting that these serum markers at baseline may have prognostic implications and be predictive of response to platinating agents. Prospective studies should validate these preliminary findings.