Working memory is frequently impaired after traumatic brain injury (TBI). The present study aimed to investigate working memory deficits in patients with diffuse axonal injury and to determine the contribution of cerebral activation dysfunctions to them. Eighteen patients with severe TBI and 14 healthy controls matched for age and gender were included in the study. TBI patients were selected according to signs of diffuse axonal injury on computed tomography (CT) and without any evidence of focal lesions on MRI clinical examination. Functional magnetic resonance (fMRI) was used to assess brain activation during n-back tasks (0-, 2-, and 3-back). Compared to controls, the TBI group showed significant working memory impairment on the Digits Backwards (p=0.022) and Letter-Number Sequencing subtests from the WAIS-III (p<0.001) under the 2-back (p=0.008) and 3-back (p=0.017) conditions. Both groups engaged bilateral fronto-parietal regions known to be involved in working memory, although patients showed less cerebral activation than did controls. Decreased activation in TBI patients compared to controls was observed mainly in the right superior and middle frontal cortex. The correlation patterns differed between patients and controls: while the control group showed a negative correlation between performance and activation in prefrontal cortex (PFC), TBI patients presented a positive correlation in right parietal and left parahippocampus for the low and high working memory load, respectively. In conclusion, severe TBI patients with diffuse brain damage show a pattern of cerebral hypoactivation in the right middle and superior frontal regions during working memory tasks, and also present an impaired pattern of performance correlations.