Background: Previous studies provide evidence for the effectiveness of web-based interventions for panic disorder with and without agoraphobia. Smartphone-based technologies hold significant potential for further enhancing the accessibility and efficacy of such interventions. Objective: This randomized controlled trial aims to evaluate the efficacy of a guided, hybrid web-based training program based on cognitive behavioral therapy for adults with symptoms of panic disorder. Methods: Participants (N=92) with total scores in the Panic and Agoraphobia Scale ranging from 9 to 28 were recruited from the general population and allocated either to a hybrid intervention (GET.ON Panic) or to a wait-list control group. The primary outcome was the reduction in panic symptoms, as self-assessed using a web-based version of the Panic and Agoraphobia Scale. Results: Analysis of covariance-based intention-to-treat analyses revealed a significantly stronger decrease in panic symptoms posttreatment (F=9.77; P=.002; Cohen d=0.66; 95% CI 0.24-1.08) in the intervention group than in the wait-list control group. Comparisons between groups of the follow-up measures at 3 and 6 months yielded even stronger effects (3-month follow-up: F=17.40, P<.001, Cohen d=0.89, 95% CI 0.46-1.31; 6-month follow-up: F=14.63, P<.001, Cohen d=0.81, 95% CI 0.38-1.24). Conclusions: Hybrid web-based training programs may help reduce the symptoms of panic disorder and hence play an important role in improving health care for patients with this debilitating disorder.