Background: Temporal lobe epilepsy (TLE) is the most common focal epilepsy subtype in adults and is frequently accompanied by depression, anxiety and psychosis. Aberrations in total paraoxonase (PON)1 status may occur in TLE and those psychiatric conditions. Methods: We examined paraoxonase (PON)1 status, namely Q192R PON1 genotypes and PON1 enzymatic activities, in 40 normal controls and 104 TLE patients, 27 without comorbidities, and 77 with comorbidities including mood disorders (n=25), anxiety disorders (n=27) and psychosis (n=25). Outcomes: CMPAase and arylesterase activities were significantly lower in TLE and mesial temporal sclerosis (MTS) with and without psychiatric comorbidities than in normal controls. The areas under the ROC curve of CMPAase were 0.893 (0.037) for TLE and 0.895 (±0.037) for MTS. Partial Least Squares (PLS) path analysis showed that there were specific indirect effects of PON1 genotype on TLE severity (p<0.0001) and psychopathology (p<0.0001), which were both mediated by lowered CMPAase activity, while arylesterase activity was not significant. The severity of TLE was significantly associated with psychopathology scores. Furthermore, PON1 CMPAase activity was inversely associated with Mini Mental State Examination scores. Interpretation: The severity of TLE and comorbidities are to a large extent explained by lowered PON1 enzyme activities and by effects of the Q192R genotype which are mediated by lowered CMPAase activity. Total PON1 status plays a key role in the pathophysiology of TLE, MTS and psychiatric comorbidities by increasing the risk of oxidative toxicity. PON1 enzyme activities are new drug targets in TLE to treat seizure frequency and psychiatric comorbidities.