The ZNF804A gene and cannabis use are risk factors for psychosis and both have also been associated with schizotypal traits. This study aimed to investigate: i) the association of lifetime cannabis use (and its dose effect) with schizotypal personality traits, and ii) whether the genetic variability at ZNF804A gene modulates that association. Our sample consisted of 385 Spanish non-clinical subjects (43.1% males, mean age = 21.11(2.19)). Schizotypy was evaluated using the three factors of the Schizotypal Personality Questionnaire-Brief (SPQ-B): Cognitive-Perceptual (SPQ-CP), Interpersonal (SPQ-I) and Disorganized (SPQ-D). Subjects were classified according to their frequency of cannabis consumption, and dichotomized as users or non-users. The effects of a genetic variant of ZNF804A (rs1344706) and cannabis use, as well as their interaction, on each of the three SPQ-B factors were assessed using linear models and permutation tests. Sex, SCL anxiety scores and use of other drugs were included as covariates. Our analysis showed a significant relationship between ZNF804A and SPQ-I: AA genotype was associated with higher scores (β = 0.885 pFDR = .018). An interaction between the AA genotype and lifetime cannabis use was found in SPQ-CP (β = 1.297 pFDR = 0.018). This interaction showed a dose–effect pattern among AA subjects: schizotypy scores increased with increasing frequency of cannabis use (sporadic users: β = 0.746 pFDR = 0.208; monthly users: β = 1.688 pFDR = 0.091; intense users: β = 1.623 pFDR = 0.038). These results add evidence on that the ZNF804A gene is associated with schizotypy and suggest that the interaction between cannabis use and ZNF804A genotype coul