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Cognitive–behavioral therapy (CBT) is a first-line treatment for panic disorder with agoraphobia (PD/AG). Nevertheless, an understanding of its mechanisms and particularly the role of therapist-guided exposure is lacking. This study was aimed to evaluate whether therapist-guided exposure in situ is associated with more pervasive and long-lasting effects than therapist-prescribed exposure in situ. A multicenter randomized controlled trial, in which 369 PD/AG patients were treated and followed up for 6 months. Patients were randomized to 2 manual-based variants of CBT (T+/T−) or a wait-list control group (WL; n= 68) and were treated twice weekly for 12 sessions. CBT variants were identical in content, structure, and length, except for implementation of exposure in situ: In the T+ variant (n= 163), therapists planned and supervised exposure in situ exercises outside the therapy room; in the T− group …