Purpose To investigate a computed tomographic (CT) protocol with iterative reconstruction at conventional radiography dose levels for the assessment of structural lung abnormalities in patients with cystic fibrosis (CF). Materials and Methods In this institutional review board-approved study, 38 patients with CF (age range, 6-58 years; 21 patients <18 years and 17 patients >18 years) underwent investigative CT (at minimal exposure settings combined with iterative reconstruction) as a replacement of yearly follow-up posteroanterior chest radiography. Verbal informed consent was obtained from all patients or their parents. CT images were randomized and rated independently by two radiologists with use of the Bhalla scoring system. In addition, mosaic perfusion was evaluated. As reference, the previous available conventional chest CT scan was used. Differences in Bhalla scores were assessed with the χ2 test and intraclass correlation coefficients (ICCs). Radiation doses for CT and radiography were assessed for adults (>18 years) and children (<18 years) separately by using technical dose descriptors and estimated effective dose. Differences in dose were assessed with the Mann-Whitney U test. Results The median effective dose for the investigative protocol was 0.04 mSv (95% confidence interval [CI]: 0.034 mSv, 0.10 mSv) for children and 0.05 mSv (95% CI: 0.04 mSv, 0.08 mSv) for adults. These doses were much lower than those with conventional CT (median: 0.52 mSv [95% CI: 0.31 mSv, 3.90 mSv] for children and 1.12 mSv [95% CI: 0.57 mSv, 3.15 mSv] for adults) and of the same order of magnitude as those for conventional radiography (median: 0.012 mSv [95% CI: 0.006 mSv, 0.022 mSv] for children and 0.012 mSv [95% CI: 0.005 mSv, 0.031 mSv] for adults). All images were rated at least as diagnostically acceptable. Very good agreement was found in overall Bhalla score (ICC, 0.96) with regard to the severity of bronchiectasis (ICC, 0.87) and sacculations and abscesses (ICC, 0.84). Interobserver agreement was excellent (ICC, 0.86-1). Conclusion For patients with CF, a dedicated chest CT protocol can replace the two yearly follow-up chest radiographic examinations without major dose penalty and with similar diagnostic quality compared with conventional CT. © RSNA, 2014.