We present a case series of 6 patients who developed persistent depersonalization disorder in adolescence after consuming cannabis. In 2 of these cases, the illness course was severely disabling. Within the growing body of literature that investigates the effects of cannabis use on mental health, the association between cannabis and depersonalization disorder is widely neglected. We review the clinical characteristics of this disorder and summarize the neurobiological evidence relating it to cannabis use. This case series extends awareness about the potentially detrimental effect of cannabis use in young individuals beyond its well-documented relationship with psychosis and other psychological sequelae.