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Background: Chronic Obstructive Pulmonary Disease (COPD) is characterised by hyperinflation and expiratory airflow limitation due to long-term exposure to irritants. The variety and complexity of COPD treatment and the possible added comorbidities may make the patients find it difficult to cope with the required medications. That’s why supporting patients' adherence is critical because not taking medications correctly increases the risk of complications and creates an additional financial burden. A range of interventions aiming to improve patient adherence were used, and most of them are complex since they involve a mix of elements. Furthermore, despite the variety of available tools, assessing adherence is challenging because clinicians usually don’t get a concrete judgement if their patients followed their treatment plan reliably. Methods: We aim to evaluate the effectiveness of adherence-enhancing interventions for COPD patients, explore which intervention (component) works for which patients and check the factors influencing the implementation and participant responses. We will include all studies investigating the effect of adherence-enhancing intervention on patients with COPD. We plan to perform two patient interviews (one before and one after the systematic review) and follow a sequential approach to integrating qualitative and quantitative information. The first interview aims to understand patients’ needs and prioritise the selection of the outcomes. The second interview will be conducted after the evidence synthesis to present the results to patients. Two reviewers with complementary expertise will perform the screening, data extraction and risk of bias assessment. We will perform two meta-analyses: the first will be pair-wise random-effects meta-analyses to combine homogeneous studies. Secondly, we will perform random-effects component network meta-analyses to identify the most effective components and combinations of components. To determine the degree of complexity, we will use the iCAT_SR checklist, and then, following a logical model, we will group the interventions according to prespecified criteria. Discussion: This systematic review aims to point out the most effective and implementable adherence-enhancing interventions by using methods for synthesising evidence on complex interventions and involving COPD patients all along with the review process. Systematic review registration: PROSPERO CRD42022353977