Aim To comprehensively examine the relationship between exposure to four classes of psychotropic drugs including antipsychotics, antidepressants, benzodiazepines (BZDs) and Z-drugs, and motor vehicle accidents (MVAs). Methods The authors conducted a matched case-control study of 5,183 subjects with MVAs and 31,093 matched controls, identified from the claims records of outpatient service visits during the period from 2000 to2009. Inclusion criteria were defined as subjects aged equal to or more than 18 years and involved in MVAs. Conditional logistic regressions with covariates adjustment (including: urbanity, psychiatric and non-psychiatric outpatient visits, and Charlson comorbidity score) were applied to examine the effect of four classes of psychotropic drugs on MVAs. Results Significant increased risk of MVAs was found in subjects taking antidepressants within one month (adjusted odds ratio (AOR)=1.73, 95% confidence interval (CI)=1.34-2.22), one week (AOR=1.71, 95%CI=1.29-2.26), and one day (AOR=1.70, 95%CI=1.26-2.29) before MVAs occurred. Similar results were observed in subjects taking benzodiazepines (BZDs) (AOR=1.56, 95%CI=1.38-1.75 for one month; AOR=1.64, 95%CI=1.43-1.88 for one week, and AOR=1.62, 95%CI=1.39-1.88 for one day) and Z-drugs (AOR=1.42, 95%CI=1.14-1.76 for one month, AOR=1.37, 95%CI=1.06-1.75 for one week, AOR=1.34, 95%CI=1.03-1.75 for one day), but not antipsychotics. Moreover, significant dose effects of antidepressants (equal to or more than 0.6-1.0 DDD), BZDs (equal to or more than 0.1-0.5 DDD), and Z-drugs (more than 1 DDD) were observed, respectively, on the risk of experiencing an MVA. Conclusions Taken together, subjects taking antidepressants, BZDs and Z-drugs, separately, should be particularly cautioned for their increasing risk of MVAs.