Importance: Posttraumatic stress disorder (PTSD) has been associated with increased mortality, primarily in studies of veterans. The World Trade Center Health Registry (Registry) provides a unique opportunity to study the association between PTSD and mortality among a population exposed to the World Trade Center attacks in New York, New York, on September 11, 2001 (9/11)., Objectives: To assess whether 9/11-related probable PTSD (PTSD) is associated with increased mortality risk, as well as whether this association differs when including repeated measures of PTSD over time vs a single baseline assessment., Design, Setting, and Participants: A longitudinal cohort study of 63 666 Registry enrollees (29 270 responders and 34 396 civilians) was conducted from September 5, 2003, to December 31, 2016, with PTSD assessments at baseline (wave 1: 2003-2004) and 3 follow-up time points (wave 2: 2006-2007, wave 3: 2011-2012, wave 4: 2015-2016). Data analyses were conducted from December 4, 2018, to May 20, 2019., Exposures: Posttraumatic stress disorder was defined using the 17-item PTSD Checklist-Specific (PCL-S) self-report measure (score ≥50) at each wave (waves 1-4). Baseline PTSD was defined using wave 1 PCL-S, and time-varying PTSD was defined using the PCL-S assessments from all 4 waves., Main Outcomes and Measures: Mortality outcomes were ascertained through National Death Index linkage from 2003 to 2016 and defined as all-cause, cardiovascular, and external-cause mortality., Results: Of 63 666 enrollees (38 883 men [61.1%]; mean [SD] age at 9/11, 40.4 [10.4] years), 6689 (10.8%) had PTSD at baseline (responders: 2702 [9.5%]; civilians: 3987 [12.0%]). Participants who were middle aged (2022 [12.5%]), female (3299 [13.8%]), non-Latino black (1295 [17.0%]), or Latino (1835 [22.2%]) were more likely to have PTSD. During follow-up, 2349 enrollees died (including 230 external-cause deaths and 487 cardiovascular deaths). Among all enrollees in time-varying analyses, PTSD was associated with all-cause, cardiovascular, and external-cause mortality, with adjusted hazard ratios (AHRs) of greater magnitude compared with analyses examining baseline PTSD. Among responders, time-varying PTSD was significantly associated with increased risk of all-cause (AHR, 1.91; 95% CI, 1.58-2.32), cardiovascular (AHR, 1.95; 95% CI, 1.25-3.04), and external-cause (AHR, 2.40; 95% CI, 1.47-3.91) mortality. Among civilians, time-varying PTSD was significantly associated with increased risk of all-cause (AHR, 1.54; 95% CI, 1.28-1.85), cardiovascular (AHR, 1.72; 95% CI, 1.15-2.58), and external-cause (AHR, 2.11; 95% CI, 1.06-4.19) mortality., Conclusions and Relevance: The risk of mortality differed in examination of baseline PTSD vs repeated measures of PTSD over time, suggesting that longitudinal data should be used where possible. Comparable findings between responders and civilians suggest that 9/11-related PTSD is associated with an increased mortality risk.