Background : The aim of this study is to examine whether treatment with roflumilast improves cognition in patients suffering from cognitive sequelae after stroke. The results may provide a proof of concept on the potential of roflumilast (or other phosphodiesterase-4 (PDE-4) inhibitors) as pharmacotherapeutic treatment to enhance cognition, and will further increase our knowledge on the role of PDE4 in human cognition in general. Cognitive processes, in particular memory, will be assessed. Methods : 100 female and male patients (41-70 years old) suffering from cognitive complaints 1 year after stroke will be recruited via advertisements via social media and via local caretaking organizations. The first phase of the study will be conducted according to a double-blind, randomized placebo-controlled, between-subjects design. After a baseline measurement, participants will be tested for acute (1 hour after drug intake) and subsequent chronic (1.5 and 3 months after start treatment) treatment effects. In a second phase, the placebo group (50 people) will be given the opportunity to receive roflumilast. This is an open label design. The roflumilast group will be tested for long-term treatment effects at three months after the end of treatment. Discussion : Strengths of the current study are the open-label design as well as the assessment of long-term effects. The findings of the current study will demonstrate if the mechanism of PDE4 inhibition is a relevant target to improve cognitive functions in patients with brain damage after a stroke. If positive effects are found in this patient group, this treatment could also be relevant for other brain disorders (e.g. head trauma, mild cognitive impairment, Fragile X syndrome, schizophrenia) in which enhanced neuronal plasticity is required to improve cognition. Trial registration : The Medical Ethics Committee of Maastricht University Medical Center+ granted ethics approval of the fourth version of the protocol on February 25, 2021. The trial was registered at the European Drug Regulatory Affairs Clinical Trials (EudraCT) register on July 29, 2020, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-003768-16 and Clinicaltrials.gov (NCT04854811) at April 21, 2021, https://clinicaltrials.gov/ct2/show/NCT04854811. The Central Committee on Research Involving Human Subjects (CCMO) granted approval on May 4, 2021.