Abstract Objective Dissociative symptoms are commonly observed during the first administration of esketamine for the treatment of Treatment-Resistant Depression (TRD) and in a substantial minority of patients with Post-Traumatic Stress Disorder (PTSD). We examine differences in the number and pattern of dissociative symptoms (depersonalization, derealization, dissociative amnesia, identity fragmentation) reported by these two groups. Data Selection Data for patients diagnosed with PTSD (N = 134) were drawn from studies of individuals with exposure to civilian traumas, childhood abuse or combat trauma. Data for patients with TRD undergoing their first treatment session with ESK (N = 759) were drawn from published results detailing the presentation of dissociative symptoms during FDA registration trials. Data Synthesis Dissociative symptoms in general were more prevalent in the ESK group (P < 0.01). However, a significant (p < 0.0001) Group x Item Domain interaction revealed that dissociative amnesia and identity fragmentation were endorsed more frequently relative to the other domains in the PTSD group relative to the ESK group. Depersonalization and derealization were the most prominent dissociative symptoms endorsed by the ESK group, whereas items from the dissociative amnesia domain were endorsed most frequently in the PTSD group. Conclusions The pattern of dissociative symptoms endorsed by patients with PTSD differs from that reported by patients with TRD receiving esketamine for the first time, suggesting the possibility that the etiology of “dissociative symptoms” may vary to some degree across therapeutic conditions.