Generic (i.e. non-branded medicine) and therapeutic (i.e. a less expensive drug from the same class) substitution of medication provides considerable financial savings, but may negatively impact on patients. We report secondary qualitative/quantitative analysis of stroke survivors from a pilot randomised controlled brief intervention to increase adherence to medication. Patients’ experiences of medication changes were examined in conjunction with electronically-recorded medication adherence. Twenty-eight patients reported frequent medication changes (e.g. size/shape/colour/packaging) and two-thirds of these reported negative effects, resulting in, at least, confusion and, at worst, mistakes in medication-taking. Patients reporting a direct effect on their medication-taking (n = 6) demonstrated poorer objectively-measured adherence (i.e. % doses taken on schedule) than those reporting confusion [mean difference = 19.9, 95 % CI (2.0, 37.8)] or no problems [mean difference = 20.6, 95 % CI (1.6, 40.0)]. Changes to medication resulting from switching between generic brands can be associated with notable problems, including poorer medication adherence, for a significant minority.