Paraoxonases and cytochromes P450 constitute two major classes of xenobiotic-metabolizing enzymes involved in the detoxification of pesticide chemicals. In this study, we examined the distribution of two common genetic polymorphisms of the paraoxonase 1 gene and one common polymorphism of the CYP1A1 gene, in relation to pathological diseases occurring in a rural population. Blood and hair samples were collected from 220 participants of an agricultural cohort in the south of Greece for genotype and pesticide analysis. Demographic information and disease status of the participants was obtained by questionnaire, medical examination and medical record. Organochlorine pesticides and metabolites (DDTs, HCHs) were extracted from hair and analyzed using gas chromatography combined with mass spectrometry techniques. Our results indicate exposure of the rural population of Amaliada to organophosphate and past exposure to organochlorine pesticides. Genotypic analysis of PON1Q192R, PON1L55M and CYP1A1*2A MspI polymorphisms was performed using PCR-RFLP. The PON1 192R and 55M alleles absence was significantly associated with hypertension (OR: 2.59; 95% CI: 1.10–6.09) and hepatitis (OR: 21.43; 95% CI: 2.53–181.50), respectively, as indicated from backward logistic regression. Although the presence of PON1 192R allele significantly affected the occurrence of prostate hyperplasia (OR: 0.35; 95% CI: 0.03–0.40), no associations were obtained between the paraoxonase serum activity or the CYP1A1 genotype and the disease status.