Background: There is growing evidence from case-control and from cohort studi es that smoking is inversely related to the risk of developing Parkinson’s dise ase (PD). However, it is still controversial if PD starts at an older age in eve r-smoking patients compared to never-smoking ones. Patients and methods: The p resent retrospective study compares in a large series of 512 outpatients,collect ed over the last 24 years, the age of onset of the complaints, the age at which PD was diagnosed and the start of levodopa treatment between ever-and never-sm okers. Also, the occurrence of long-term side-effects of the drug was evaluate d.184 PD patients with a history of smoking were compared with 328 who had never smoked. The subgroups with and without a family history of PD were analysed sep arately. Results: In the overall ever-smoking group, as well as in the subgroup without a family history, the onset of the disease and the time of the diagnosi s of PD and the time at which levodopa was started occurred at an older age than in the never-smoking group. This difference could not be demonstrated in the p atients with a family history, due to the low number of cases and the lack of st atistical power. Although the follow-up period was the same in both study group s, motor fluctuations and dyskinesia were more frequent and appeared earlier aft er levodopa treatment in the non-smoki- ng compared to the ever-smoking PD patients.Only for cognitive impairment the re was a non-significant trend in the smoking group. Conclusion: The present st udy confirms the protective action of smoking on PD and also suggests some modul ating effect of smoking on the dopaminergic system. Background: There is growing evidence from case-control and from cohort studi es that smoking is inversely related to the risk of developing Parkinson’s disease a (PD). However, it is still controversial if PD starts at an older age in eve r-smoking patients compared to never-smoking ones. Patients and methods: The p resent retrospective study compares in a large series of 512 outpatients, collect ed over the last 24 years, the age of onset of the complaints, the age at which PD was diagnosed and the start of levodopa treatment between ever-and never-sm okers. Also, the occurrence of long-term side-effects of the drug was evaluated d.184 PD patients with a history of smoking were compared with 328 who had never smoked. Results: In the overall ever-smoking group, as well as in the subgroup without a family history, the onset of the disease and the time of the diagnosi s of PD and the time at which levodopa was started occurred at an older age than in the never-smoking group. This difference could not be demonstrated in the p atients with a family history, due to the low number of cases and the lack of st atistical power. was the same in both study group s, motor fluctuations and dyskinesia were more frequent and earlier aft er levodopa treatment in the non-smoki-ng compared to the ever-smoking PD patients. For cognitive impairment the re was a non-significant trend in the smoking group. Conclusion: The present st udy confirms the protective action of smoking on PD and also suggests some modul ating effect of smoking on the dopaminergic system.