Abstract Background Multiple parameters influence adherence to drug treatment, including socio-economic, healthcare, condition, therapy, and patient-related factors. However, studies of the impact of patient-related factors, particularly regarding comorbid conditions, have produced conflicting results. Objectives To analyse the association between mental and physical comorbidity and non-adherence to antihypertensive medication in patients attending primary care, after including a comprehensive range of chronic comorbidities and potential confounders. Methods Cross-sectional study of 113,397 adults with a diagnosis of hypertension in 2010 assigned to the public health service of a region in northeastern Spain. Pharmacy billing records were linked to data from electronic health records at individual level. Non-adherence was defined as an antihypertensive medication possession ratio (MPR) < 80%. Multivariable logistic regression models were used to estimate the odds ratio for non-adherence. Potential predictors included mental and physical comorbidity, age, sex, blood pressure level, nationality, rurality, polypharmacy, and number of visits to the GP and to different specialties. Results One fifth of the study population showed poor adherence levels. Female sex, younger age, foreign nationality, living in a rural area, low blood pressure levels, polypharmacy, and mental comorbidity were positively and significantly associated with non-adherence. Conversely, non-adherence was negatively and significantly associated with the presence of cardiovascular risk factors and higher annual rates of GP visits. Conclusion The majority of patient-related determinants identified here (e.g., the presence of mental comorbidity, polypharmacy, foreign nationality) underscores the need for a patient- rather than a disease-centred care approach, as well as adequate physician-patient communication.