BACKGROUND: In light of clinical reports suggesting that early benzodiazepine administration interferes with long-term recovery from traumatic stress, a prospective animal model for PTSD was employed to assess the short- and long-term effects of a brief course of alprazolam following stress exposure. Method: Animals exposed to stress were treated either 1 h or 7 days later with alprazolam or vehicle for 3-days. Outcome measures included behavior in the elevated plus-maze (EPM) and acoustic startle response (ASR) tests 30 days after initial exposure and freezing behavior upon exposure to a trauma-cue on day 31. One group was repeatedly exposed to the triggering trauma shortly before and after treatment and assessed as above. Circulating corticosterone levels were assessed 4 h after initiation of alprazolam and post-treatment. Pre-set cut-off behavioral criteria classified exposed animals according to their EPM and ASR response-patterns into 'extreme', 'minimal,' or 'partial' behavioral response for analysis of prevalence rates. Results: Immediate alprazolam treatment was effective in alleviating anxiety at day 4. No observable anxiolytic effects remained at day 30. Immediate alprazolam also resulted in significantly greater freezing response to trauma-cue exposure and in extreme responses to double-exposure. Corticosterone levels were significantly suppressed by alprazolam during treatment and rebounded after cessation. Conclusion: A brief course of alprazolam in the immediate aftermath of stress-exposure is associated with less favorable responses to additional stress-exposure later on. Alprazolam was associated with a significant attenuation of the HPA-response, suggesting a possible link between initial HPA-axis response disruption and the subsequent unfavorable outcomes.