To evaluate the associations of a polygenic risk score and healthy lifestyle with incident stroke. Prospective population based cohort study. UK Biobank Study, UK. 306 473 men and women, aged 40-73 years, recruited between 2006 and 2010. Hazard ratios for a first stroke, estimated using Cox regression. A polygenic risk score of 90 single nucleotide polymorphisms previously associated with stroke was constructed at P<1×10 to test for an association with incident stroke. Adherence to a healthy lifestyle was determined on the basis of four factors: non-smoker, healthy diet, body mass index <30 kg/m , and regular physical exercise. During a median follow-up of 7.1 years (2 138 443 person years), 2077 incident strokes (1541 ischaemic stroke, 287 intracerebral haemorrhage, and 249 subarachnoid haemorrhage) were ascertained. The risk of incident stroke was 35% higher among those at high genetic risk (top third of polygenic score) compared with those at low genetic risk (bottom third): hazard ratio 1.35 (95% confidence interval 1.21 to 1.50), P=3.9×10 . Unfavourable lifestyle (0 or 1 healthy lifestyle factors) was associated with a 66% increased risk of stroke compared with a favourable lifestyle (3 or 4 healthy lifestyle factors): 1.66 (1.45 to 1.89), P=1.19×10 . The association with lifestyle was independent of genetic risk stratums. In this cohort study, genetic and lifestyle factors were independently associated with incident stroke. These results emphasise the benefit of entire populations adhering to a healthy lifestyle, independent of genetic risk.