Background <p>Evidence describing the patient-reported symptom burden of influenza infection remains limited. This study assessed prevalence and symptom severity over one-month post-infection during the high-severity 2024–2025 United States (U.S.) season.</p> Methods <p>Symptomatic adults ≥ 18 years with positive influenza tests were recruited nationwide from ambulatory care clinic sites in a U.S. national clinic network from 10/24/2024 to 4/24/2025. Participants prospectively completed a symptom survey daily from Days 1 through 7, Day 10, Day 14, and Week 4 after enrollment. Day 1 included retrospective reporting of the worst moment since infection and pre-influenza symptoms (baseline). Prevalence and severity of 12 acute influenza-related symptoms were assessed using a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). A composite score was derived by summing ratings across 12 symptoms. Adjusted mixed models for repeated measures estimated the longitudinal impact of influenza infection on symptom burden. Least squares estimates (LSEs) were used to derive mean change and standard error (SE) at each timepoint relative to baseline. Effect size (ES) was calculated using Cohen’s d.</p> Results <p>The analysis included 724 adults (mean (standard deviation [SD]) age: 42.0 [13.0] years), 74.2% female, 49.3% vaccinated against influenza, and 27.6% had ≥ 1 comorbidity. On Day 1, the mean composite symptom score was 17.1 (SE: 0.3), with an average of 8.7 total symptoms (SE: 0.1), 5.9 moderate-to-severe (SE: 0.1), and 2.5 severe symptoms (SE: 0.1). At Week 4, there were mean increases of 0.5 points in composite symptom score (SE: 0.2), 0.3 in any symptoms (SE: 0.1), and 0.2 in moderate-to-severe symptoms (SE: 0.1) compared to pre-infection. Severe symptoms persisted through Day 5, with a mean increase of 0.2 (SE: 0.1) on Day 5.</p> Conclusion <p>Influenza infection was associated with a high symptom burden that peaked in the first days of illness but extended over four weeks. Severe symptoms decreased over time, becoming moderate or mild, although milder symptoms were still reported at Week 4. These findings highlight the burden of influenza and reinforce the importance of strategies to mitigate this burden including vaccination and other preventive interventions.</p> Trial registration <p>The study was first registered on <a href="https://clinicaltrials.gov/">ClinicalTrials.gov</a> (NCT05160636) on 12/15/2021.</p>