Aims To explore the clinical features of methamphetamine‐induced paranoia (MIP) and associations between MIP and a genetic polymorphism in dopamine β‐hydroxylase (DBH‐1021C→T). Design Retrospective analysis of clinical presentation and genetic association by χ2 test and logistic regression analysis. Setting A Thai substance abuse treatment center. Participants A total of 727 methamphetamine‐dependent (MD) individuals. Measurements Clinical: Semi‐Structured Assessment for Drug Dependence and Alcoholism (SSADDA) and the Methamphetamine Experience Questionnaire (MEQ). Genetic: DBH‐1021C→T. Findings Forty per cent of individuals (289 of 727; 39.8%) with MD had MIP. Within‐binge latency to MIP onset occurred more rapidly in the most recent compared with initial MIP episode (P = 0.02), despite unchanging intake (P = 0.89). Individuals with MIP were significantly less likely to carry lower (TT/CT) compared with higher (CC) activity genotypes (34.3 versus 43.3%; χ21 = 5, P = 0.03). DBH effects were confirmed [odds ratio (OR) = 0.7, P = 0.04] after controlling for associated clinical variables (MD severity, OR = 3.4, P < 0.001; antisocial personality disorder, OR = 2.2, P < 0.001; alcohol dependence, OR = 1.4, P = 0.05; and nicotine dependence, OR = 1.4, P = 0.06). TT/CT carriers were more likely to initiate cigarette smoking (OR = 3.9, P = 0.003) and probably less likely to be dependent on alcohol (OR = 0.6, P = 0.05). Conclusions Among methamphetamine‐dependent individuals, paranoia appears to occur increasingly rapidly in the course of a session of methamphetamine use. Severity of methamphetamine dependence and antisocial personality disorder predicts methamphetamine‐induced paranoia. The genetic polymorphism in dopamine β‐hydroxylase is associated with methamphetamine‐induced paranoia and influences smoking initiation.