ObjectivesIn order to understand the influencing factors of the medication-taking behaviour in patients with chronic diseases, reveal the deep-seated causes underlying the phenomenon of polypharmacy, explore the formation rules of the risk perception of polypharmacy and how risk perception affect the medication decision-making behaviour of patients with chronic diseases.DesignA qualitative descriptive design was used. Study data were collected through semi-structured interviews with patients and physicians. We used the grounded theory approach to refine influencing factors, followed by interpretative structural modelling that analysed the interaction between these factors.SettingPatients from two hospitals, two nursing homes and two communities. Physicians from two community hospitals in Wuhan, China.ParticipantsPatients with chronic diseases with high willingness to cooperate and good communication ability. Physicians with rich experience in the treatment of chronic diseases.ResultsTwenty-nine interviews were conducted (20 patients and 9 physicians). A total of 35 influencing factors of the medication-taking behaviours in patients with chronic diseases were extracted from the interview data, further integrated into 10 integrated influencing factors and ultimately clustered into three aspects: ‘medication benefit’, ‘medication risk’ and ‘medication strategy’. Medication risk can be divided into four specific dimensions: economic risk, physical risk, psychosocial risk and time risk. 10 integrated influencing factors constituted the interpretative structural model of the medication decision-making behaviours in patients with chronic diseases.ConclusionsThe causes underlying the medication decision-making behaviour of patients with chronic diseases are complex, involving a series of influencing factors such as their risk perception of the medication-taking behaviour. In order to alleviate the adverse effects of polypharmacy on patients’ health and medical costs, further safety measures should be proposed to improve the medication-taking behaviour in patients with chronic diseases based on the relationship and internal mechanism of the influencing factors of the medication decision-making behaviour.