Background A proportion of patients presenting with acute small ischemic strokes have poor functional outcomes, even following rapid recanalization treatment. Aims Infarct growth may occur even after successful recanalization and could represent an appropriate endpoint for future stroke therapy trials. Methods Magnetic resonance diffusion-weighted imaging lesion volumes were obtained at 5 h (initial posttreatment) and 24 h (follow-up) after acute stroke treatment for n = 33 in ischemic stroke patients. Sample sizes per arm (90% power, 30% effect size) for diffusion-weighted imaging lesion growth between initial and 24 h, early change in the National Institutes of Health Stroke Scale between pre- and 24 h, National Institutes of Health Stroke Scale at 24 h, and diffusion-weighted imaging lesion volume at 24 h were estimated to power a placebo-controlled stroke therapy trial. Results For patients with poor recanalization (modified thrombolysis in cerebral infarction <2 a; modified arterial occlusion lesion = 0–2) (n = 11), the median diffusion-weighted imaging lesion growth was 8.1 (interquartile range: 4.5, 22.4) ml and with good recanalization (modified thrombolysis in cerebral infarction =2 b or 3; modified arterial occlusion lesion = 3) (n = 22), the median diffusion-weighted imaging lesion growth was 10.0 (interquartile range: 6.0, 28.2) ml ( P = 0.749). When considering a 30% effect size, the sample size required per arm to achieve significance in an acute stroke study would be: (1) N = 49 for the diffusion-weighted imaging lesion growth between initial posttreatment and follow-up time points, (2) N = 65 for the change in the National Institutes of Health Stroke Scale between admission and 24 h, (3) N = 259 for the National Institutes of Health Stroke Scale at 24 h, and (4) N = 256 for diffusion-weighted imaging volume at 24 h. Conclusion Despite best efforts to recanalize the ischemic brain, early diffusion-weighted imaging lesion growth still occurs. Treatment trials in stroke should consider early diffusion-weighted imaging lesion growth as a surrogate outcome measure to significantly reduce sample sizes.