Objective: To examine the causal relevance of lifelong differences in LDL-C for ischaemic stroke (IS) relative to that for coronary heart disease (CHD) using a Mendelian randomization approach. Methods: We undertook a two-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information from 62 independent genetic variants with genome-wide significant effects on LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and CHD for heterogeneity. Results: A 1 mmol/L higher genetically-determined LDL-C was associated with a 50% higher risk of CHD (OR: 1.49, 95%CI: 1.32-1.68, p=1.1x10-8). By contrast, the causal effect of LDL-C was much weaker for IS (OR: 1.12, 95%CI: 0.96-1.30, p=0.14; p for heterogeneity=2.6x10-3) and, in particular, for cardioembolic stroke (OR: 1.06, 95%CI: 0.84-1.33, p=0.64; p for heterogeneity=8.6x10-3) when compared with that for CHD. Conclusions: In contrast with the consistent effects of LDL-C lowering therapies on IS and CHD, genetic variants that confer lifelong LDL-C differences show a weaker effect on IS than on CHD. The relevance of aetiologically distinct IS subtypes may contribute to the differences observed.