Background: Among older adults with cancer receiving chemotherapy, frailty indices can predict poor outcomes including survival and toxicity. Given the increasing use of immunotherapy and targeted therapy to treat NSCLC, we assessed the prognostic importance of frailty among older adults with NSCLC receiving systemic therapy. Methods: This multi-site prospective cohort study enrolled adults age ≥65 with advanced NSCLC starting chemotherapy, immunotherapy, and/or targeted therapy with non-curative intent. Patients completed geriatric assessments pretreatment and at 1, 2, 4, and 6 months. We constructed a 47-item deficit-accumulation frailty index including pretreatment demographic, geriatric assessment, and clinical factors using established methodology. Frailty scores ranged from 0 (no frailty deficits) to 1 (all frailty deficits present). We categorized patients as robust ( < 0.2), pre-frail (0.2-0.34), or frail (≥0.35). The primary outcome was OS. Secondary outcomes included treatment-related grade ≥3 adverse events (AE), unplanned hospitalization, and functional decline in instrumental activities of daily living (IADL). We conducted a Kaplan-Meier survival analysis to estimate OS by frailty group and Cox proportional hazards models adjusting for treatment type. We used logistic regression models to evaluate the association of frailty with secondary outcomes adjusting for treatment type. Results: Among 149 patients, median age was 73 (range 65-94). During the study, 32% received targeted therapy, 29% immunotherapy, 27% chemoimmunotherapy, and 12% chemotherapy. Overall 43% of patients were robust, 38% pre-frail, and 19% frail. Frailty was associated with Asian race, lower education, Medicaid insurance, and no prior NSCLC surgery. Notably, frailty was not associated with age or treatment type. Median OS was 18.7 months overall: not reached for robust patients, 8.9 months for pre-frail, and 5.6 months for frail patients. Adjusting for treatment type, pre-frail (HR 2.11, 95% CI 1.24-3.60; p = 0.006) and frail (HR 2.86, 95% CI 1.52-5.39; p = 0.001) patients had worse OS compared to robust patients. During treatment, 29% developed a grade ≥3 AE, 31% had an unplanned hospitalization, and 41% developed IADL decline. Pre-frail/frail patients were more likely to develop IADL decline (HR 2.18, 95% CI 1.02-4.68; p = 0.04) than robust patients, but there were no differences in toxicity or hospitalization. Conclusions: Frailty is prognostic for OS among older adults with advanced NSCLC receiving systemic therapy across treatment types and predicted IADL decline. Frailty assessment before initiation of systemic therapy may help identify older adults with advanced NSCLC at higher risk of poor outcomes to inform decision making, individualize anticipatory guidance, and optimize supportive care.