PURPOSE: Our objective was to measure the trajectory of financial distress and to determine its relationship with quality of life (QOL) among patients with cancer. MATERIALS AND METHODS: We conducted a longitudinal survey of patients with gynecologic cancer starting a new line of systemic therapy at baseline, 3 months, and 6 months. Financial distress was measured using a Comprehensive Score for Financial Toxicity (COST) < 26, and QOL was measured using Functional Assessment of Cancer Therapy-General (FACT-G) with lower scores indicating worse responses. One-way repeated analysis of variances, generalized estimating equation models, and correlation coefficients were used to evaluate financial distress and QOL over time. RESULTS: There were 90 of 121 (74%) baseline participants with a 6-month follow-up. The average age was 60 years, 29% were African-American, 57% had an annual income < $40,000 in US dollars, and 6% were uninsured. At baseline, 54% of patients screened positive for financial distress, which was unchanged at 3 months (50%, P = .27) but decreased at 6 months (46%, P = .04) compared with baseline. There was no change in average COST (23.6, 25.1, 25.6; P = .33) or FACT-G (70.8, 71.0, 72.8; P = .68) over time. Less financial distress was moderately correlated with better QOL (r = 0.63, 0.61, 0.60) at each time point. The presence of financial distress was associated with a 16-point decrease in FACT-G QOL score over time. CONCLUSION: Upfront screening with COST identified 90% of patients who experienced financial distress, and COST did not change significantly over time. More severe financial distress was moderately correlated with worse QOL, and its presence was associated with a clinically meaningful 16-point decrease in QOL.