Background The human paraoxonase (PON1) protein detoxifies certain organophosphates, and the PON1 Q192R polymorphism (rs662) affects PON1 activity. Groups with higher dose exposure to organophosphate sheep dips or first Gulf War nerve toxins reported poorer health if they had 192R, and these associations have been used to exemplify Mendelian randomization analysis. However, a reported association of 192R with depression in a population-based study of older women recently cast doubt on the specificity of the higher dose findings. We aimed to examine associations between the PON1 Q192R polymorphism and self-reported poor health and depression in two independent population-based studies. Methods We used logistic regression models to examine the associations in men and women aged 60–79 years from the English Longitudinal Study of Ageing (ELSA, n = 3158) and InCHIANTI (n = 761) population studies. Outcomes included the Center for Epidemiologic Studies Depression (CES-D) scale, self-rated general health status and (in ELSA only) diagnoses of depression. Results The PON1 Q192R polymorphism was not associated with self-reported poor health {meta-analysis: odds ratio (OR) = 1.01 [confidence interval (CI) 0.91–1.13], P = 0.80} or depressive symptoms in either study or in meta-analyses [CES-D: OR = 1.01 (CI 0.87–1.17), P = 0.90]. There was also no association with histories of diagnosed depression in ELSA [OR = 1.03 (CI 0.82–1.30), P = 0.80]. Conclusions We found no evidence of an association between the PON1 Q192R polymorphism and poor general or mental health in two independent population-based studies. Neither the claimed Q192R association with depression in the general population nor its theoretical implications were supported.