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Increased rates of atypical handedness are observed in neurotypical individuals who are low-performing in mathematical tasks as well as in individuals with special educational needs, such as dyslexia. This is the first investigation of handedness in individuals with Mathematical Learning Difficulties (MLD). We report three new studies ( N  = 134; N  = 1,893; N  = 153) and two sets of meta-analyses (22 studies; N  = 3,667). No difference in atypical hand preference between MLD and Typically Achieving (TA) individuals was found when handedness was assessed with self-report questionnaires, but weak evidence of a difference was found when writing hand was the handedness criterion in Study 1 ( p  = .049). Similarly, when combining data meta-analytically, no hand preference differences were detected. We suggest that: (i) potential handedness effects require larger samples, (ii) direction of hand preference is not a sensitive enough measure of handedness in this context, or that (iii) increased rates of atypical hand preference are not associated with MLD. The latter scenario would suggest that handedness is specifically linked to language-related conditions rather than conditions related to cognitive abilities at large. Future studies need to consider hand skill and degree of hand preference in MLD.