Purpose A range of strategies to improve pharmaceutical care has been implemented by population health management (PHM) initiatives. However, which strategies generate the desired outcomes is largely unknown. The purpose of this paper is to identify guiding principles underlying collaborative strategies to improve pharmaceutical care and the contextual factors and mechanisms through which these principles operate. Design/methodology/approach The evaluation was informed by a realist methodology examining the links between PHM strategies, their outcomes and the contexts and mechanisms by which these strategies operate. Guiding principles were identified by grouping context-specific strategies with specific outcomes. Findings In total, ten guiding principles were identified: create agreement and commitment based on a long-term vision; foster cooperation and representation at the board level; use layered governance structures; create awareness at all levels; enable interpersonal links at all levels; create learning environments; organize shared responsibility; adjust financial strategies to market contexts; organize mutual gains; and align regional agreements with national policies and regulations. Contextual factors such as shared savings influenced the effectiveness of the guiding principles. Mechanisms by which these guiding principles operate were, for instance, fostering trust and creating a shared sense of the problem. Practical implications The guiding principles highlight how collaboration can be stimulated to improve pharmaceutical care while taking into account local constraints and possibilities. The interdependency of these principles necessitates effectuating them together in order to realize the best possible improvements and outcomes. Originality/value This is the first study using a realist approach to understand the guiding principles underlying collaboration to improve pharmaceutical care.