Abstract Background: Cue exposure (CE) is used for relapse prevention as part of smoking cessation therapy to reduce the automatized response to smoking-related cues. Using CET in virtual reality (VR) is an approach to increase its efficacy by creating cost-efficient high-risk situations. The efficacy of VR-based CETs was compared to that of an unspecific relaxation intervention as an add-on to an established cognitive-behaviorally oriented smoking cessation group therapy (G-CBT). Methods: N=246 abstinence-motivated smokers were included in a two-armed randomized controlled trial (G-CBT with VR-CET vs. G-CBT with progressive muscle relaxation/PMR) with 1-, 3-, and 6-month follow-ups (measurements in 2018-2020). All smokers joined a well-established G-CBT smoking cessation program with six sessions of two additional therapies: four sessions of VR-based smoking cue exposure therapy (VR-CET) and four sessions of group-based PMR. The primary outcome was abstinence after 6 months according to the Russell Standard; secondary outcomes were the number of smoked cigarettes, craving (assessed by the Questionnaire of Smoking Urges/QSU), and self-efficacy (assessed by the Smoking Abstinence Self-Efficacy Scale/SES). Results:Primary outcome: Six months after G-CBT, 24% of the participants were abstinent, and there was no significant difference between the PMR (n=34/124) and VR-CET (n=24/122) groups (odds ratio (PMR)/VR = 0.64). Secondary measures: SES increased, and QSU and the number of smoked cigarettes decreased over time. Baseline craving ratings predicted abstinence only in the VR-CET group. Discussion:Compared with G-CBT combined with PMR, G-CBT combined with VR-CET did not improve smoking cessation rates. This result is possibly related to an insufficient amount of training in the subgroup of smokers with intense initial cravings. Conclusion: This randomized controlled trial did not show increased abstinence rates related to smoking cue exposure in virtual reality. However, maximum baseline cravings revealed a predictive value for abstinence in the VR group. This may indicate that the amount of training was insufficient and should be intensified. Individualization, e.g., adaptive, individualized approaches, is required to improve the effects of the VR-CET on smoking cessation in future studies. Trial Registration: ClinicalTrials.gov Identifier: NCT03707106