Background White matter hyperintensities (WMH) are commonly seen on in brain imaging, and are associated with stroke and cognitive decline. Therefore, they may provide a relevant intermediate outcome in clinical trials. WMH can be measured as a volume or visually on the Fazekas scale. We investigated predictors of WMH progression and design of efficient studies using WMH volumes and Fazekas score as an intermediate outcome. Methods We prospectively recruited 264 patients with mild ischaemic stroke and measured WMH volumes, Fazekas score, age, and cardiovascular risk factors at baseline and 1 year. We modelled predictors of WMH burden at 1 year and used the results in sample size calculations for hypothetical randomised controlled trials with different analysis plans and length of follow-up. Results Follow-up WMH volume was predicted by baseline WMH - a 0.73ml (95%CI 0.65 to 0.80, p<0.0001) increase per 1ml baseline volume increment, and 2.93ml increase (95%CI 1.76 to 4.10, p<0.0001) per point on the Fazekas scale. Using a mean difference of 1ml in WMH volume between treatment groups, 80% power, and 5% alpha, adjusting for all predictors and 2 year follow-up produced the smallest sample size (642). Other study designs produced samples sizes from 2054 to 21270. Sample size calculations using Fazekas scores as outcome using the same power and alpha, and an odds ratio corresponding to a 1ml difference were sensitive to assumptions, and ranged from 2504 to 18886. Conclusions Baseline WMH volume and Fazekas scores predict follow-up WMH volume. Study size was smallest using volumes and longer term follow-up, but this must be balanced against resources required to measure volumes versus Fazekas scores, bias due to drop-out and scanner drift. Samples sizes based on Fazekas scores may be best estimated with simulation studies.