Introduction Viral infections are associated with pulmonary exacerbations in children with Cystic Fibrosis (cwCF), but after 3 years of SARS-CoV-2 pandemic, whether cwCF are at higher risk of developing COVID-19 or its adverse consequences remains controversial. Methods We conducted an observational, multicenter, cross-sectional study of cwCF infected by SARS-CoV-2 between March 2020 and June 2022, (1 st to 6 th COVID-19 pandemic waves) in Spain. The study aimed to describe patients’ basal characteristics, SARS-CoV-2 clinical manifestations and outcomes, and whether there were differences across the pandemic waves. Results During study time, 351 SARS-CoV2 infections were reported among 341 cwCF. Median age was 8.5 years (range 0-17) and 51% were female. Cases were unevenly distributed across the pandemic, with most cases (82%) clustered between November 2021 and June 2022 (6 th wave, also known as Omicron Wave due to the higher prevalence of this strain in that period in Spain). Most cwCF were asymptomatic (24.8%) or presented with mild Covid-19 symptoms (72.9%). Among symptomatic, most prevalent symptoms were fever (62%) and increased cough (53%). No multisystem inflammatory syndrome (MIS-C), persisting symptoms, long-term sequelae or deaths were reported. Conclusions Spanish current data indicate that cwCF do not experience higher risks of SARS-CoV-2 infection nor worse health outcomes or sequelae. Changes in patients’ basal characteristics, clinical courses and outcomes were detected across waves. While the pandemic continues, and new SARS-CoV-2 variants are being identified, a worldwide monitoring of COVID-19 in pediatric CF patients is needed.