Introduction: Although the effects of proximal smoking cues have been widely studied in smokers, little is known on the features associated with background spatial context effect, that is, “context reactivity.” The aim of this study was to investigate context reactivity exhibited by smokers in virtual cue-free domestic scenarios. Methods: Sixty-nine participants divided in 2 cohorts (33 smokers and 36 non-smokers) were exposed to a virtual reality session with 4 domestic room scenarios presented in a balanced order: bedroom, bathroom, kitchen, and living room. Results: We showed that (i) it is possible to elicit smoking craving in smokers in virtual reality, and (ii) these effects are room dependent and (iii) associated with a lower sense of presence; furthermore, (iv) smokers reported higher craving scores for alcohol and food in a room-dependent fashion compared to non-smokers. Conclusion: Our study provides an experimental paradigm for assessing context reactivity in smokers and suggests a potential use for the identification of non-pharmacological interventions as a co-adjuvant of smoking cessation treatment.