OBJECTIVE: This study aimed to determine if the activity of the environmentally influenced cytochrome P450 enzyme CYP1A2, alone or in combination with CYP2D6*4 genotype, discriminates subgroups of oral lichen planus (OLP) according to lifestyle factors and clinical manifestations. STUDY DESIGN: A total of 111 patients with OLP were categorized according to normal, low, or high CYP1A2 activity and CYP2D6 4 genotype. Lifestyle parameters influencing the CYP1A2 activity and symptoms and manifestations of OLP were recorded. RESULTS: Of the 111 patients, 21% had low, 65% normal, and 14% high CYP1A2 activity. The high-CYP1A2-activity group was more exposed to CYP1A2 inducers than the low-CYP1A2-activity group. In the normal-CYP1A2-activity group, more patients had a CYP2D6 4 genotype (58%) (P = .02), and they presented more symptoms (P = .003) and gingival lesions (P = .03). More patients in the low-CYP1A2-activity group and without CYP2D6 4 genotype presented red lesions (P = .04). CONCLUSIONS: We suggest CYP2D6 4 genotype as a disease-susceptible genotype and low or high CYP1A2 activity levels as indicators of environmental influence in OLP subgroups.