Background Initial studies have provided a mixed perspective of the efficacy of d‐cycloserine (DCS) for augmenting the efficacy of exposure‐based cognitive behavioral therapy (CBT) for panic disorder. In this multicenter trial, we examine the magnitude of DCS augmentation effects for an ultra‐brief program of CBT. Methods We conducted a double‐blind, controlled trial at three treatment sites, randomizing 180 adults with a primary diagnosis of panic disorder to five sessions of treatment, with study pill (50 mg DCS or matching placebo) administered 1 hr prior to the final three sessions. Two booster sessions were subsequently provided, and outcome was assessed at posttreatment and 1‐month, 2‐month, and 6‐month follow‐up assessments. The primary outcome was the degree of reduction in the Panic Disorder Severity Scale. Additional analyses examined the role of severity and current antidepressant or benzodiazepine use as moderators of DCS augmentation effects. Results DCS augmentation resulted in significant benefit only early in the trial, with no beneficial effects of DCS augmentation evident at follow‐up evaluations. We did not find that baseline severity or antidepressant or benzodiazepine use moderated DCS efficacy, but benzodiazepine use was associated with lower efficacy of CBT regardless of augmentation condition. Conclusions Consistent with other recent multicenter trials, the benefit of DCS was less than indicated by pilot study and reflected an acceleration of treatment response evident at treatment endpoint, but no advantage in response over follow‐up evaluation. Our results did not support severity or concomitant medication moderators observed in previous trials of DCS augmentation.