The recently published results of the NETTER-2 trial suggest the use of [Lu]Lu-DOTATATE as a new standard of care in first-line therapy of patients with grade 2 or 3, well-differentiated, advanced gastroenteropancreatic neuroendocrine tumors. The NETTER-2 trial found superior median progression-free survival (22.8 mo vs. 8.5 mo) and similar adverse events and quality-of-life measures in patients treated with [Lu]Lu-DOTATATE compared with octreotide long-acting release (LAR) alone. As [Lu]Lu-DOTATATE therapy is associated with higher costs, we compared the cost-effectiveness of [Lu]Lu-DOTATATE with that of octreotide LAR in this setting. A partitioned survival model was established for the trial duration of 36 mo as well as a lifetime horizon of 20 y. Progression-free survival and treatment regimens for each patient group were derived from the NETTER-2 trial. Information on overall survival as well as utilities for health states and utilities and costs of adverse events were obtained from the literature. Information on treatment costs was obtained from the Centers for Medicare and Medicaid Services. The willingness-to-pay threshold was set to $100,000 per quality-adjusted life-year (QALY). [Lu]Lu-DOTATATE was cost-effective during the trial duration, with an incremental QALY of 0.13 at a slightly higher cost ($8,931), leading to an incremental cost-effectiveness ratio of $66,761/QALY. For the lifetime analysis, [Lu]Lu-DOTATATE dominated treatment with octreotide LAR. However, deterministic sensitivity analysis revealed that the incremental cost-effectiveness ratio was strongly influenced by the percentage of patients treated with [Lu]Lu-DOTATATE after disease progression as well as number of cycles of [Lu]Lu-DOTATATE they received after progression. In the probabilistic sensitivity analysis using Monte Carlo simulation with 10,000 iterations, [Lu]Lu-DOTATATE proved to be the most cost-effective strategy for 64% of Monte Carlo iterations over the trial duration. [Lu]Lu-DOTATATE is cost-effective as a first-line treatment for patients with grade 2 or 3, well-differentiated, advanced gastroenteropancreatic neuroendocrine tumors.