23 Background: Patients undergoing definitive radiation therapy (RT) for head and neck cancer (HNC) are at risk for financial toxicity given complex treatment and high symptom burden. The PaRTNer study was designed to longitudinally assess out-of-pocket (OOP) expenses, financial toxicity (FT), and quality of life (QOL). Methods: Single-institution, prospective longitudinal study (NCT3506451) of adult patients with non-metastatic HNC undergoing definitive RT. Surveys at baseline, 3 mo, and 6 mo post-RT collected validated QOL and FT measures (FACT-HN and COST-FACIT [COST score <26 indicating FT]) and OOP expenses. Retrospective chart review documented social work (SW) and financial care counselor (FCC) interactions. Paired t-tests, Wilcoxon Rank Sum tests, ANOVA, and Spearman correlation estimates were used to assess associations in outcomes. Results: 60 patients were enrolled from 2019-2021, with 80% completing all 3 surveys. Most were white (76%), male (68%), and non-Hispanic (98%). Median age was 61 (range 42-86). Most were married or in long-term partnerships (69%), had completed at least some college (71%), and had employer-sponsored private insurance (55%). About half were working at least part-time, and most earned >$60k/yr (55%); median annual income was $88k (Range: $6k-800k). Median COST scores at baseline, 3 mo, and 6 mo post-RT were 25, 30, and 32, respectively (p<0.001, baseline vs 6 mo). Median cumulative OOP expense was $6,909 (Range: $0-43,572). Cumulative OOP expense had a weakly positive correlation with income (r=0.39, p=0.024), but did not significantly correlate with COST scores. 33% were referred to SW; these patients had lower mean COST scores at baseline compared to patients not referred to SW (16 vs 28, p=0.0007). 38% were referred to FCC, with no significant difference in baseline COST scores (20 vs 26, p=0.07). Median FACT-HN score decreased from baseline to 3 mo (117 to 110, p=0.03) and increased from 3 to 6 mo (110 to 115.5, p=0.0007); there was no difference between baseline and 6 mo post-RT. Those with lower COST scores had lower median FACT-HN scores at all 3 time points (108 vs 124, p=0.001; 99 vs 107, p=0.006; 100 vs 122, p=0.0006 at baseline, 3 mo, and 6 mo respectively). There was a positive correlation between baseline OOP expense and FACT-HN score (r=0.497, p=0.0002), which did not persist at 3 or 6 mo post-RT. Conclusions: This small longitudinal study found that patients undergoing definitive RT for HNC experienced FT at baseline; however, this improved post-RT. Patients paid several thousand dollars OOP over the course of RT and recovery, but OOP expenses did not appear to drive worse FT or QOL. Designing patient-facing interventions including facilitated referral to SW or FCC could help those with significant FT, but defining the optimal population and intervention time point requires further study. Clinical trial information: NCT3506451 .