Importance There is a pressing need for development of novel pharmacology for the treatment of Posttraumatic Stress Disorder (PTSD). Given increasing use of medical cannabis among US military veterans to self-treat PTSD, there is strong public interest in whether cannabis may be a safe and effective treatment for PTSD. Objective The aim of the present study was to collect preliminary data on the safety and potential efficacy of three active concentrations of smoked cannabis (i.e., High THC = approximately 12% THC and Methods The study used a double-blind, cross-over design, where participants were randomly assigned to receive three weeks of either active treatment or placebo in Stage 1 (N = 80), and then were re-randomized after a 2-week washout period to receive one of the other three active treatments in Stage 2 (N = 74). The primary outcome measure was change in PTSD symptom severity from baseline to end of treatment in Stage 1. Results The study did not find a significant difference in change in PTSD symptom severity between the active cannabis concentrations and placebo by the end of Stage 1. All three active concentrations of smoked cannabis were generally well tolerated. Conclusions and relevance The present study is the first randomized placebo-controlled trial of smoked cannabis for PTSD. All treatment groups, including placebo, showed good tolerability and significant improvements in PTSD symptoms during three weeks of treatment, but no active treatment statistically outperformed placebo in this brief, preliminary trial. Additional well-controlled and adequately powered studies with cannabis suitable for FDA drug development are needed to determine whether smoked cannabis improves symptoms of PTSD. Trial registration Identifier: NCT02759185; ClinicalTrials.gov.