Macrophagic myofasciitis (MMF) is an emerging condition characterized by specific muscle lesions assessing abnormal long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients usually are middle-aged adults, mainly presenting with diffuse arthromyalgias, chronic fatigue, and marked cognitive deficits, not related to pain, fatigue, or depression. Clinical features usually correspond to that observed in chronic fatigue syndrome/myalgic encephalomyelitis. Representative features of MMF-associated cognitive dysfunction include dysexecutive syndrome, visual memory impairment, and left ear extinction at dichotic listening test. Most patients fulfill criteria for non-amnestic/dysexecutive mild cognitive impairment, even if some cognitive deficits appear unusually severe. Cognitive dysfunction seems stable over time despite marked fluctuations. Evoked potentials may show abnormalities in keeping with central nervous system involvement, with a neurophysiological pattern suggestive of demyelination. Brain perfusion SPECT shows a pattern of diffuse cortical and subcortical abnormalities, with hypoperfusions correlating with cognitive deficiencies. The combination of musculoskeletal pain, chronic fatigue, and cognitive disturbance generates chronic disability with possible social exclusion. Classical therapeutic approaches are usually unsatisfactory making patient care difficult.