This study evaluated the effectiveness of quetiapine for subjects with post-traumatic stress disorder (PTSD) who were already on a stable dose of a selective serotonin reuptake inhibitor (SSRI) but had significant PTSD symptoms. Fifteen subjects were enrolled in an 8-week open-label trial for PTSD in which quetiapine was added to an SSRI. Subjects were on a stable dose of the SSRI for at least 6 weeks before study entry and had a Clincian-Administered PTSD Scale (CAPS) score of greater than or equal to 50 at study baseline. The mean age of subjects was 49 years (eight men and seven women). The average duration of PTSD was 29 years, one-third of subjects had combat-related PTSD, and two-thirds had noncombat PTSD. The mean dose prescribed in the study was 216 mg per day. The initial median CAPS score was 80, indicating severe PTSD. The addition of a modest dose of quetiapine provided significant relief from PTSD symptoms with a 42% overall improvement in PTSD symptoms based on the CAPS and significant improvement along each dimension of symptoms: re-experiencing (Z=-3.24, P=0.0012), hyperarousal (Z=-3.30, P=0.001) and avoidance (Z=-2.13, P=0.03). Subjects rated themselves as 45% improved on average on the Davidson Trauma Scale and reported a 44% decrease in their level of disability and impairment as reflected by the Sheehan Disability Scale. Subjects with PTSD who had significant PTSD symptoms when on an SSRI benefited from the addition of quetiapine. Patients improved significantly on all three clusters of PTSD symptoms: re-experiencing, hyperarousal and avoidance.