BACKGROUND: Pharmacists' clinical decision-making is considered a core process of pharmaceutical care in pharmacy practice, but little is known about the factors influencing this process. OBJECTIVE: To identify factors influencing clinical decision-making among pharmacists working in pharmacy practice. METHODS: Semi-structured interviews were conducted with pharmacists working in primary, secondary, and tertiary care settings in the Netherlands between August and December 2021. A thematic analysis was conducted using an inductive approach. The emerged themes were categorized into the Capability-Opportunity-Motivation-Behaviour (COM-B) model domains. RESULTS: In total, 16 pharmacists working in primary care (n = 7), secondary care (n = 4) or tertiary care (n = 5) were interviewed. Factors influencing pharmacists' capability to make clinical decisions are a broad theoretical knowledge base, clinical experience, and skills, including contextualizing data, clinical reasoning, and clinical judgment. The pharmacy setting, data availability, rules and regulations, intra- and interprofessional collaboration, education, patient perspectives, and time are mentioned as factors influencing their opportunity. Factors influencing pharmacists' motivation are confidence, curiosity, critical thinking, and responsibility. CONCLUSIONS: The reported factors covered all domains of the COM-B model, implying that clinical decision-making is influenced by a combination of pharmacists' capability, opportunity, and motivation. Addressing these different factors in pharmacy practice and education may improve pharmacists' clinical decision-making, thereby improving patient outcomes