Background: The treatment (tx) landscape for patients (pts) with metastatic melanoma (MM) has changed dramatically from systemic chemotherapy (chemo) to novel therapies, including targeted therapies (TT) and immunotherapies (IO mono- and combination therapy) in recent years. Healthcare resource utilization (HCRU) and cost data are needed to further evaluate tx in a value-based healthcare system. The study aimed to describe HCRU and total cost of care among first line (1L) US MM pts treated with IO, TT, or chemo. Methods: A retrospective observational study was conducted using a U.S. claims database. Adults with ≥2 claims for melanoma and ≥1 claim for metastasis between January 1, 2012 and June 30, 2017 were identified. Pts had pharmacy and medical enrollment ≥6 months pre and ≥3 months post 1L tx start. Per pt per month (PPPM) HCRU and costs were calculated by 1L tx drug class: PD-1, CTLA-4, CTLA-4+PD-1, mono-TT, combo-TT, and chemo. Adjusted odds ratios (OR) for HCRU were estimated by logistic regressions, and adjusted costs were estimated by generalized linear models to control for differences in pt characteristics across groups. Results: Among 1,599 MM pts (255 PD-1, 555 CTLA-4, 88 CTLA-4+PD-1, 210 mono-TT, 102 combo-TT, 389 chemo), mean age ranged from 59–68 years across tx groups, and the majority was male (62%). Any hospitalization during 1L was less frequent among PD-1 (26%) compared to 35%–46% of all other groups (all P<.05). CTLA-4, CTLA-4+PD-1, and combo-TT had increased odds of hospitalization compared to PD-1 (adjusted ORs: 2.10, 2.35, 2.15, respectively; all P<.05). Total adjusted PPPM costs were significantly lower for PD-1 compared to CTLA-4, CTLA-4+PD-1 and combo-TT and higher compared to mono-TT and chemo (). Conclusions: Hospitalizations represent an important healthcare resource for MM pts and were lowest among PD-1. Total monthly costs varied substantially across 1L regimens and were significantly lower in PD-1 compared to CTLA-4, CTLA-4+PD-1, and combo-TT. HCRU and costs differentiate 1L MM regimens.