It has been shown that long-term stimulant consumption alters the biological and microbiological status of the oral cavity. We present a pilot study describing stimulant-specific oral immunomodulation in the oral cavity. Changes in salivary cytokine levels in response to long-term alcohol, tobacco and caffeine were identified. Volunteers were recruited from amongst the patients visiting University Dental Clinic of CEU Cardenal Herrera University (Alfara del Patriarca, Spain). Participants were grouped according to their self-reported levels of consumption of either caffeine, alcohol or tobacco (control group volunteers were non-consumers of all three). Informed consent was provided and stimulated saliva samples were obtained and assayed for interleukin-1α IL-1α), Tumor Necrosis Factor α (TNF-α) and Interferon γ IFN-γ). Long-term, high-level consumers of alcohol or tobacco exhibited elevated salivary concentrations of the three inflammatory cytokines with respect to control values. Specifically, IL-1α was found to be elevated in alcohol users whilst IFN-γ concentration higher in tobacco users versus controls. Long-term caffeine consumers displayed elevated levels of IFN-γ and TNF-α, whereas IL-1α levels were reduced with respect to control volunteers. This pilot study demonstrates that salivary cytokines can be modulated in response to quantity and duration of alcohol, caffeine or tobacco consumption.