Objectives: Sheep-dippers report an acute flu-like condition (dippers' flu: DF) but the cause and relation to chronic disability are unknown. Methods: In a case-referent study previously reported, 175 sheep dippers with chronic disability and 234 referents, sheep dippers in good health, completed an interview with information on dipping, type of pesticide used and health for each year 1970-2000 and gave blood for typing of PON1 polymorphisms. Results: Reports of DF were much higher (66.3% 116/ 175) in the chronically unwell than in those without chronic ill-health (18.0% 42/234: OR=8.99 95% CI 5.69-14.21). No significant relation was seen between reported exposures and DF in those with chronic illness, but risk was higher with concentrate handling in those without. An R allele at position 192 on PON1 related to reports of DF both in those with chronic illness (OR=2.04 95% CI 1.08-3.87) and in those who started dipping after 1969 and were not chronically unwell (OR=2.52 95%CI 1.00-6.37). Interaction between handling diazinon concentrate and PON1 (192R) increased the risk of DF. No precipitating factor was identified in a case-crossover analysis. In the group without chronic illness those with 192R developed DF earlier (risk ratio 2.49 95%CI 1.03-6.02). Conclusion: 'Dippers' flu' and chronic ill-health attributed to dipping share a common polymorphism (192R). The interaction between handling diazinon concentrate and PON1 genotype supports the conclusion that organophosphates may cause DF. Sheep dippers who are still healthy but experience 'dippers' flu' may be wise to further limit exposures to organophosphates.