Background & Aims: Shortening the treatment duration for chronic hepatitis C may increase feasibility and reduce the cost of cure. The aims of this study were to compare 4 weeks of glecaprevir/pibrentasvir (GLE/PIB) treatment with and without ribavirin for patients with chronic hepatitis C and favourable baseline characteristics and to monitor the development of resistance-associated substitutions (RAS) and re-treatment outcomes if treatment failed. Methods: We performed an open-label single-centre randomized controlled trial, in which patients with chronic hepatitis C were randomized 1:1 to GLE/PIB ± ribavirin, stratified by genotype 3. The main inclusion criteria were treatment-naive patients, aged 18-49 with all genotypes accepted, and absence of liver fibrosis, determined by liver stiffness measurement less than 8 kPa. Viral genome sequences were determined by deep sequencing at baseline and at the time of relapse. Results: A total of 32 patients started treatment. Sustained virological response at week 12 (SVR12) was 59% (10/17) for GLE/PIB without ribavirin and 73% (11/15) for GLE/PIB with ribavirin. Drug target-specific NS5A RAS were detected at baseline for 45% (5/11) of patients with treatment failure and for 14% (3/21) of patients who achieved SVR12. Ten failure patients were retreated 12 weeks with sofosbuvir-based regimens; all have been cured. Conclusions: In this pilot study of 4-week treatment with GLE/PIB with and without ribavirin, we found that baseline RAS were more frequent in patients with virological failure. Development of RAS did occur after short treatment but did not result in retreatment failure with a different regimen. EudraCT no: 2017-005179-21.