BackgroundThe Symptoms of Infection with Coronavirus-19 (SIC) is a 30-item patient-reported outcome (PRO) measure scored by body system composites to assess signs/symptoms of coronavirus disease 2019 (COVID-19). In addition to cross-sectional and longitudinal psychometric evaluations, qualitative exit interviews were conducted to support the content validity of the SIC.MethodsIn a cross-sectional study, adults diagnosed with COVID-19 in the United States completed the web-based SIC and additional PRO measures. A subset was invited to participate in phone-based exit interviews. Longitudinal psychometric properties were assessed in ENSEMBLE2, a multinational, randomized, double-blind, placebo-controlled, phase 3 trial of the Ad26.COV2.S COVID-19 vaccine. Psychometric properties evaluated included structure, scoring, reliability, construct validity, discriminating ability, responsiveness, and meaningful change thresholds of SIC items and composite scores.ResultsIn the cross-sectional study, 152 participants completed the SIC (mean age, 51.0 ± 18.6 years) and 20 completed follow-up interviews. Fatigue (77.6%), feeling unwell (65.8%), and cough (60.5%) were symptoms most frequently reported. SIC inter-item correlations were all positive and mostly moderate (r ≥ 0.3) and statistically significant. SIC items and Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) scores correlated as hypothesized (all r ≥ 0.32). Internal consistency reliabilities of all SIC composite scores were satisfactory (Cronbach’s alpha, 0.69–0.91). SIC composite scores correlated moderately (r = 0.30–0.49) to strongly (r ≥ 0.50) with PROMIS-29 scores and Patient Global Impression of Severity (PGIS) ratings (allP< 0.01). A variety of signs/symptoms were cited in exit interviews, and participants considered the SIC straightforward, comprehensive, and easy to use. From ENSEMBLE2, 183 participants with laboratory-confirmed moderate to severe/critical COVID-19 were included (51.5 ± 14.8 years). Strong test-retest reliabilities were observed for most SIC composite scores (intraclass correlations ≥ 0.60). Statistically significant differences across PGIS severity levels were found for all but 1 composite score, supporting known-groups validity. All SIC composite scores demonstrated responsiveness based on changes in PGIS.ConclusionsThe psychometric evaluations provided strong evidence for the reliability and validity of the SIC for measuring COVID-19 symptoms, supporting its use in vaccine and treatment trials. In exit interviews, participants described a broad range of signs/symptoms consistent with previous research, further supporting the content validity and format of the SIC.Supplementary InformationThe online version contains supplementary material available at 10.1186/s41687-023-00581-z.