OBJECTIVES: We compared complications, costs, and health care resource utilization (HCRU) of patients with newly diagnosed metastatic nonsmall-cell lung cancer (mNSCLC) who had a tissue biopsy followed by either liquid biopsy (TFLB) (identified with a novel algorithm) or tissue re-biopsy (TRB). METHODS: This claims-based retrospective analysis included commercial and Medicare Advantage members in the Optum Research Database with mNSCLC (January 2017 to June 2021) and ≥2 tissue biopsy claims (7 to 90 d apart) (TRB) or ≥1 tissue and ≥1 liquid biopsy claim within 90 days (TFLB). Patients in the TFLB group were matched 1:1 to patients in the TRB group using propensity score matching. Surgical biopsy-related complications and complication-related and all-cause medical costs and HCRU during the 6-month follow-up were compared. RESULTS: Both groups had 235 patients post-match. During the follow-up, the surgical biopsy-related complication rate was lower in the TFLB group than the TRB group (65.1% [153/235] vs. 84.7% [199/235], P <
0.001). Mean complication-related medical costs were significantly lower with TFLB (494 vs. 9,741, P <
0.001) during the follow-up
mean (SD) duration of complication-related inpatient stays was significantly lower with TFLB (3.5 [7.0] vs. 6.6 [13.3] d, P =0.002). Mean all-cause medical costs were not significantly different between the groups
the TFLB group had fewer all-cause inpatient stays, inpatient days, and outpatient visits. CONCLUSIONS: Multiple tissue biopsy procedures may be associated with significantly higher biopsy complication rates, higher complication-related medical costs, and longer complication-related inpatient stays than TFLB. All-cause medical costs were similar between groups.