This study assesses resource utilization and total direct medical cost among patients in the United States starting systemic antineoplastic therapy (ST) pre- and postapproval of immuno-oncology (IO) agents for advanced non-small cell lung cancer. Adults diagnosed with lung cancer initiating first-line ST within 6 months of diagnosis during either the pre- (March 2013-March 2014) or post-IO (March 2015-December 2016) approval period were identified in a US-based multipayer administrative claims database. Excluded were patients with small cell lung cancer, secondary malignancies, less than 1 month follow-up, and those in clinical trials. Total cost (TC) was calculated from the date of initiation of treatment until the last follow-up. Propensity score matching was adjusted for differences in patient cohorts, including follow-up time. Binary multiple logistic regression assessed predictors of high TC (above mean) pre- and post IO. Mean TC per patient was higher pre-IO versus post IO in both unmatched ($165,548 vs $95,715) and matched analyses($129,977 vs $113,177). Hospitalization and emergency department (ED) visit rates were higher pre-IO versus postapproval. Predictors of high TC pre-IO included use of first-line combination therapy, radiation, targeted therapy, maintenance therapy, biomarker testing, more comorbidities, longer follow-up, first-line hospitalization, first-line cost above mean, and age 65 years and older. In the post-IO period, additional predictors of higher TC included use of IO, having mild liver disease or hemiplegia, and longer time to ST initiation. Early data show lower ED visit and hospitalization rates and associated lower TC in the post-IO era.