Background: Lung cancer is the second most common cancer diagnosed in the United States. An estimated 236,740 new cases of lung cancer were diagnosed in 2022. Use of genomic testing to drive treatment decisions can lead to improvements in patient survival. However, the HCRU and costs of genomic testing are just being understood and little is known about the impact of the clinical relevance of those genomic findings. Methods: This retrospective analysis utilized administrative claims and enrollment information with linked genomic sequencing results from Optum’s de-identified Market Clarity Data and Clinicogenomics Database. Adult lung cancer patients newly diagnosed between 01 January 2016 – 30 June 2021 with evidence of treatment and genomic sequencing results post diagnosis were eligible for the study. Patients were required to have at least 6 months of continuous enrollment prior to and after their diagnosis date, unless death occurred, and were followed until death, disenrollment, or study end. Cohorts were created based on presence of clinically relevant variants with an FDA-approved treatment for lung cancer. Unadjusted all-cause HCRU and costs during follow-up were reported as per-patient per-month (PPPM). Results: This study identified 2,190 patients, of which 999 (45.6%) had clinically relevant variants. Age, insurance type, and geographic region did not appear to differ substantially between groups, though those with clinically relevant variants were more likely to be female (57.4% vs. 46.0%). During follow-up, the average number of PPPM ambulatory visits was similar between groups (5.89 vs. 5.58, p = 0.08), but the average number of emergency room visits (0.29 vs. 0.23, p < 0.01) and inpatient stays (0.12 vs. 0.11, p = 0.03) were higher among those with clinically relevant variants. Additionally, those with clinically relevant variants had higher average PPPM all-cause medical costs ($20,948 vs. $19,097; p = 0.02) and pharmacy costs ($3,073 vs. $2,083, p = 0.02). Conclusions: Average PPPM emergency room visits, inpatient stays, medical costs and pharmacy costs were higher among lung cancer patients with clinically relevant variants compared to those with non-clinically relevant variants. Future research should evaluate HCRU and costs attributable to targeted therapy.