Background: The evidence base for trauma-focused cognitive behavioral therapy (TF-CBT) to treat posttraumatic stress disorder (PTSD) in youth is compelling, but the number of controlled trials in very young children is few and limited to sexual abuse victims. These considerations plus theoretical limitations have led to doubts about the feasibility of TF-CBT techniques in very young children. This study examined the efficacy and feasibility of TF-CBT for treating PTSD in three- through six-year-old children exposed to heterogeneous types of traumas. Methods: Procedures and feasibilities of the protocol were refined in Phase 1 with 11 children. Then 64 children were randomly assigned in Phase 2 to either 12-session manualized TF-CBT or 12-weeks wait list. Results: In the randomized design the intervention group improved significantly more on symptoms of PTSD, but not on depression, separation anxiety, oppositional defiant, or attention deficit/hyperactivity disorders. After the waiting period, all participants were offered treatment. Effect sizes were large for PTSD, depression, separation anxiety, and oppositional defiant disorders, but not attention-deficit/hyperactivity disorder. At six-month follow-up, the effect size increased for PTSD, while remaining fairly constant for the comorbid disorders. The frequencies with which children were able to understand and complete specific techniques documented the feasibility of TF-CBT across this age span. The majority were minority race (Black/African-American) and without a biological father in the home, in contrast to most prior efficacy studies. Conclusions: These preliminary findings suggest that TF-CBT is feasible and more effective than a wait list condition for PTSD symptoms, and the effect appears lasting. There may also be benefits for reducing symptoms of several comorbid disorders. Multiple factors may explain the unusually high attrition, and future studies ought to oversample on these demographics to better understand this understudied population.