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Background: Few studies have explored whether high-anticholinergic load may hamper rehabilitation in persons with schizophrenia. We aim to explore the associations between anticholinergic load of psychotropic treatment and functioning or cognitive performances of persons with psychosis engaged in psychosocial rehabilitation. Methods: The study was performed using data collected at baseline assessment in the REHABase cohort including persons referred to a French network of psychosocial rehabilitation centers. The composite-rating scale developed by Salahudeen et al. was used to rate the anticholinergic load of psychotropic drugs prescribed at baseline assessment. The associations between total anticholinergic load score (categorized as 'low' <3 v. 'high' ⩾3) and functioning or cognitive characteristics were explored using multivariate analyses. Results: Of the 1012 participants with schizophrenia spectrum disorders identified in the REHABase, half used at least two psychotropic drugs with anticholinergic activity and one out of three was prescribed at least one psychotropic drug with high-anticholinergic activity. High-anticholinergic load was significantly associated with lower stage of recovery [odds ratio (OR) = 1.70, 95% confidence interval (CI) 1.05–2.76, p = 0.03], poor mental well-being (OR = 1.55, 95% CI 1.02–2.33, p = 0.04) and poor self-rated medication adherence (OR = 2.14, 95% CI 1.29–3.53, p = 0.003). Regarding cognition, a high-anticholinergic score was associated with poorer delayed-episodic memory (OR = 1.69, 95% CI 1.01–2.85, p = 0.05) and at the trend level with faster completion time on the test exploring executive performance (OR = 0.67, 95% CI 0.43–1.04, p = 0.07). Conclusions: The psychosocial rehabilitation plan of persons with psychosis should integrate optimization of psychotropic treatment in order to lessen the functional and cognitive impact of high-anticholinergic load. [ABSTRACT FROM AUTHOR]