Clinical Practice Guidelines (CPGs) represent evidence-based tools designed to assist healthcare practitioners and patients in decisions in clinical practice. Evidence supports the clinical benefits of adhering to CPGs. However, their successful implementation and adherence in clinical settings often encounter challenges. This systematic review aimed to explore barriers and facilitators influencing adherence to CPGs in Germany. The protocol of this study was registered in the Open Science Framework (OSF) registry (DOI: 10.17605/OSF. IO/GMFUB). In November 2022 we searched on PubMed and Embase for primary studies employing qualitative, quantitative and mixed-methods approaches that focus on barriers or facilitators to CPGs adherence in the Germany. Two reviewers independently screened articles, extracted data, and evaluated the quality of the studies. The collected data on barriers and facilitators of CPG adherence were systematically categorized and analyzed using the Theoretical Domains Framework (TDF). A total of 24 studies were included, mainly focusing on adherence to national CPGs. This review introduces a new domain, guideline characteristics, reflecting the need to address barriers and facilitators to CPG development, implementation, dissemination and format, which couldn't be encompassed within the existing 14 domains of TDF framework. Among healthcare professionals, the most frequently reported influencing factors were related to the environmental context and resources (encompassing aspects such as employer support for CPG utilization), the CPG development and dissemination process (including layout, wording, and interactive tools) and beliefs about consequences (such as contradictions with practical experience). Knowledge (knowledge about the content of CPGs, awareness about published CPGs), primarily as a barrier, and reinforcement facilitators (notably financial support), were also frequently reported. The findings revealed multilevel factors contributing to CPG adherence, with environmental context and resources emerging as the most frequently reported considerations. This systematic review offer holistic insights into the barriers and facilitators of CPG adherence in Germany. The results contribute to a better understanding of the topic and serve as a resource for developing targeted strategies to enhance CPG adherence and implementation within the German healthcare system.