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BACKGROUND Scant evidence exists on the long-term course of cancer-related post-traumatic stress disorder (PTSD). This is among the few studies worldwide, and the first in the South-East Asian region, to prospectively evaluate PTSD in patients with cancer using gold-standard clinical interviews. The objective of the study was to assess the course and predictors of PTSD in adult patients with cancer in a South-East Asian population. METHODS A prospective, longitudinal study was conducted in a cohort of 469 consecutively recruited patients (aged ≥18 years) with various cancer types within 1 month of diagnosis at a single oncology referral center. Only patients who had significant psychological distress (Hospital Anxiety and Depression Scale total cutoff score ≥16) underwent the PTSD module of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (SCID) at at 6-months follow-up. All patients completed the SCID at the 4-year follow-up assessment regardless of their initial Hospital Anxiety and Depression Scale score. RESULTS In an analysis combining patients who had both full and subsyndromal PTSD, there was a 21.7% incidence of PTSD at the 6-month follow-up assessment (n = 44 of 203 SCID-interviewed patients), with rates dropping to 6.1% at the 4-year follow-up assessment (n = 15 of 245 SCID-interviewed patients). Patients with breast cancer (compared with those who had other types of cancer) were 3.68 times less likely to develop PTSD at 6-months, but not at 4-years follow-up. CONCLUSIONS The overall rates of PTSD decreased with time, but one-third of patients (34.1%) who were initially diagnosed had persistent or worsening PTSD 4 years later. There is a need for early identification of this subset of patients who have cancer with PTSD to design risk-targeted interventions. Cancer 2018;124:406-16. © 2017 American Cancer Society.