Background: Preoperative oral capecitabine plus radiotherapy has been progressively adopted in oncology units to provide more convenient care to patients with rectal cancer, but little is known about adherence to this therapy. Patients and methods: Prospective, multicentre observational study in six hospitals in metropolitan Barcelona (Spain), in patients with stage II and III rectal cancer. Assessment of adherence was based on the medical report in the clinical history, a patient questionnaire and a pill count in the pharmacy service upon finalization of treatment. Patients were considered adherent if they had taken 80%-110% of the prescribed treatment. We evaluated clinical variables, adverse effects, anxiety and depression (using the hospital anxiety depression scale [HADS]), and quality of life (EORTC QLQ-30). We analysed adherence-associated variables using a logistic regression model and concordance between adherence measures by means of the modified Kappa index. Results: We included 119 participants. Adherence measures showed little concordance between the assessment methods used: adherence was 100% according to the clinical history, 83.2% according to self-report and 67.9% according to the pill count. In the multivariable analysis, the most relevant variable associated with non-adherence was anxiety prior to treatment (adjusted odds ratio [ORa] 6.96, 95% confidence interval [CI] 1.48-32.7). We did not observe any relevant association between adherence and clinical variables and baseline quality of life parameters. Conclusions: Adherence to short-term oral neoadjuvant treatment in rectal cancer may be a clinical problem, and it should be acknowledged and systematically evaluated by clinicians during treatment. The limited concordance between different measures of adherence highlights the challenges in monitoring it and the need to use different approaches to assess its impact in clinical practice.