Background: Neuroleptics are commonly used in palliative care settings. However, adverse events of neuroleptics, known as extrapyramidal symptoms (EPSs), might be overlooked in clinical practice. We conducted this study to explore the prevalence of EPSs in palliative care setting. Methods: This multicenter, prospective, observational study included patients who 1) were referred to either a specialist palliative care team or a palliative care unit, 2) had a diagnosis of cancer, and 3) were ≥20 years of age. We investigated the prevalence of EPSs and medications used. The primary outcome was the overall Drug-Induced Extrapyramidal Symptom Scale (DIEPSS) score. Results: Between November 2015 and October 2016, 149 patients from 5 centers in Japan were enrolled. The median age was 67 years (range: 21–88 years) and the study population included 81 men (54.4%). The cancer types included lung (55 patients, 36.9%), upper gastrointestinal tract (5, 3.3%), hepatobiliary (19, 12.8%); breast (12, 8.1%); head and neck (10, 6.7%), gynecologic (10, 6.7%), genitourinary (10, 6.7%), and others (28, 18.8%). The median Karnofsky performance status was 60 (20–100). Most patients (86.6%) did not experience delirium. Thirty-nine (26.2%) patients received one or more EPS-inducing medications. EPSs occurred in 4 (2.7%) patients with a cutoff score of 5 points for 5 parkinsonism items in DIEPSS. Conclusion: A lower frequency (<3%) of patients than expected in this population had EPSs. Therefore, we concluded that an interventional study is not feasible. However, medications that cause EPSs are often used in palliative care; therefore, a longitudinal study is warranted. Trial registration: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) (UMIN000019810) on 16, November, 2015.