OBJECTIVES: In the treatment of schizophrenia, antiparkinsonian agents (APKs) are customarily used to counteract drug-induced reversible movement disorders such as extrapyramidal symptoms in order to facilitate adherence to antipsychotic regimens. Unfortunately, in addition to beneficial effects, APKs were shown to cause other adverse effects such as cognitive impairment. This study prospectively examined the role of APKs in self-reported medication-related cognitive impairment and akathisia (subjective or objective restlessness) among patients treated over a 3-year period in usual care with olanzapine or risperidone. METHODS: Using data from a 3-year observational study of schizophrenia, we included olanzapine (N = 372) and risperidone (N = 229) treated patients who continued on index medication for at least 1-year post enrollment. Medication use was based on medical records. Self-reported medication-related cognitive impairment and akathisia were assessed with validated instruments. Analysis included mixed models adjusted for covariates. RESULTS: Utilization rates of APKs were almost twice as high among risperidone than olanzapine-treated patients (p = 0.001). When not receiving APKs, akathisia was significantly worse for risperidone than olanzapine-treated patients, and rates of akathisia were comparable when receiving APKs. However, when receiving APKs, risperidone-treated patients reported significant increases in cognitive impairment compared to olanzapine-treated patients (p = 0.0198). CONCLUSIONS: In this naturalistic 3-year study, freedom from adjunctive antiparkinsonian agents was associated with worse akathsia for risperidone than olanzapine-treated patients. Moreover, use of antiparkinsonian agents was linked to worsening of self-reported cognitive impairment for risperidone but not for olanzapine-treated patients. Further studies are needed to examine this phenomenon.