To determine whether the rich-club organization, essential for information transport in the human connectome, is an important biomarker of functional outcome after acute ischemic stroke (AIS). Consecutive AIS patients ( = 344) with acute brain magnetic resonance imaging (MRI) (<48 h) were eligible for this study. Each patient underwent a clinical MRI protocol, which included diffusion weighted imaging (DWI). All DWIs were registered to a template on which rich-club regions have been defined. Using manual outlines of stroke lesions, we automatically counted the number of affected rich-club regions and assessed its effect on the National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS; obtained at 90 days post-stroke) scores through ordinal regression. Of 344 patients (median age 65, inter-quartile range 54-76 years) with a median DWI lesion volume (DWIv) of 3cc, 64% were male. We established that an increase in number of rich-club regions affected by a stroke increases the odds of poor stroke outcome, measured by NIHSS (OR: 1.77, 95%CI 1.41-2.21) and mRS (OR: 1.38, 95%CI 1.11-1.73). Additionally, we demonstrated that the OR exceeds traditional markers, such as DWIv (OR 1.08, 95%CI 1.06-1.11; OR 1.05, 95%CI 1.03-1.07) and age (OR 1.03, 95%CI 1.01-1.05; OR 1.05, 95%CI 1.03-1.07). In this proof-of-concept study, the number of rich-club nodes affected by a stroke lesion presents a translational biomarker of stroke outcome, which can be readily assessed using standard clinical AIS imaging protocols and considered in functional outcome prediction models beyond traditional factors.