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Objective: To conduct a comprehensive review of the literature on factors determining cooperation in pharmacological treatment in people with schizophrenia. Method: A systematic review of the MEDLINE and PsycINFO databases for papers published from 1969 to 2024 was performed. Prospective, cross-sectional and retrospective studies as well as meta-analyses meeting methodological quality criteria were included in the analysis. Results: The percentage of non-cooperative patients ranges from approximately 20% to 56% in the literature, with an average level close to 41%. The most commonly identified predictors of non-cooperation are poorer insight into the illness, younger age, psychoactive substance use, and greater severity of positive and negative symptoms. Non-cooperation is associated with a significantly higher risk of relapse and rehospitalisation, as well as poorer social and occupational functioning. Positive attitudes towards pharmacotherapy, a good therapeutic relationship, and family support improve cooperation regardless of the level of insight, which justifies combining psychoeducational, relational, and environmental interventions with the optimization of pharmacological treatment. Conclusions: Cooperation in pharmacological treatment is a key, modifiable factor in the course of schizophrenia. Effective strategies require a multidimensional approach that includes psychoeducation, psychosocial support, improvement of the therapeutic alliance, minimisation of adverse effects, and the introduction of simpler and more convenient treatment plans. Further well-designed, prospective studies evaluating the long-term effectiveness of interventions that increase cooperation are needed.