Poststroke fatigue (PSF) is frequent and affects patients' quality of life. Medication use was hypothesized as being responsible for PSF. Our objective was to evaluate potential relationships between 6-month PSF and medication use at discharge and 6 months after an ischemic stroke. This study is part of STROKDEM, an ongoing longitudinal cohort study, whose main aim is to determine predictors of poststroke dementia. Patients were included within 72 hours after an ischemic stroke and followed up with standardized evaluations. Medication use 7 days and 6 months after stroke was rated, and polypharmacy was defined as the number of categories of treatments received by a patient. PSF was evaluated using the Chalder Fatigue Scale. Medical history, vascular risk factors, depression, anxiety, and sleep disturbances were evaluated. One hundred and fifty-three patients were included: 52.9% presented PSF. PSF at 6 months was not predicted by medication use at discharge nor associated with medication use at month 6. We found severity of PSF to be increased in patients with polypharmacy. Our results suggest that PSF is not a side effect of drugs use, which more reflects presence of disturbances frequently observed after stroke such as depression, anxiety, or sleep disturbances. Clinical study is registered on clinicaltrials.gov (NCT01330160).