The epidemiology of motor neurone disease (MND) in the counties of Devon and Cornwall in the southwest of England has not previously been studied. A previous study of England and Wales has, however, reported a very high death certification rate of MND in Devon. This study was carried out to establish the prevalence and incidence of MND in Devon and Cornwall and make comparisons with published rates in other populations. We attempted to identify all cases of MND diagnosed in Devon and Cornwall between 2002 and 2007. Case identification was centred on the major hospitals in the two counties and multiple sources of ascertainment were used. All identified cases had their case notes reviewed to establish the diagnosis and classify by type of MND. Point prevalence of MND was established for September 1st, 2007. The overall incidence rate standardised to the 2001 United Kingdom population was 2.52 per 100,000 (95% confidence interval 2.20-2.84). The incidence rate was significantly higher in males (P < 0.001). The estimated male to female incidence ratio was 2.10 (95% CI 1.61-2.73). The crude incidence rate in Cornwall was 3.78 per 100,000 (95% CI 3.03-4.53) and this was significantly higher (P = 0.011) than the rate in Devon, which was 2.61 per 100,000 (95% CI 2.19-3.04). The standardised incidence rate for the study period in Devon was 2.26 per 100,000 (95% CI 1.91-2.60) and in Cornwall it was 3.06 per 100,000 (95% CI 2.44-3.68). The overall standardised point prevalence rate was 5.66 per 100,000 (95% CI 4.49-6.83). The incidence rate of MND in our study is similar to reported findings in large prospective studies of the disease. There is a significant difference between the incidence rates in Devon and Cornwall. There is a need to establish a prospective MND Register to accurately document the epidemiological characteristics of the disease in the two counties.