Many studies have shown a protective effect of cigarette smoking on Parkinson's disease. However, criticism has been raised concerning confounding by genetic factors. We investigated the associations between Parkinson's disease and smoking, alcohol, coffee, area of living, and education in a co-twin control study. Because twins are matched for genetic and familial environmental factors, this design controls for confounding by these factors. We also examined control subjects unrelated to cases. Exposure information was taken from questionnaires answered in the 1960s and 1970s. Parkinson's disease cases were identified through the Swedish Inpatient Discharge Register (IDR) and the Cause of Death Register. In the unrelated control subject comparison, 476 Parkinson's disease cases and 2,380 control subjects were included. In the co-twin control comparison, 415 same-sex twin pairs were included. There was an inverse association between smoking and Parkinson's disease using unrelated control subjects and co-twin control cases. There was no association between Parkinson's disease and alcohol, coffee, or area of living. High educational level was associated with Parkinson's disease in the unrelated control subject comparison but not in the co-twin control comparison. We confirm the protective effect of smoking on Parkinson's disease and establish that the association is only partially explained by genetic and familial environmental factors. Ann Neurol 2004