In traumatic brain injury (TBI), cerebral edema and hemorrhage are factors involved in the determination of the clinical presentation and outcome. The aquaporin 4 (AQP4) water channel is abundant in mammalian brain and there is a growing body of evidence suggesting that this protein plays a major role in the control of water flow within the central nervous system. Previous studies examined the influence of genetic variants in cerebral edema of TBI. However, to our knowledge, there are no previous studies of molecular variations of the AQP4 gene and its association with TBI. Thus, we sought to investigate if the clinical presentation and outcome of TBI could be influenced by the presence of mutations on exon 4 of the AQP4 gene. One hundred and two patients were enrolled in this study. A neurologist assessed the clinical severity at admission according to the GCS followed by a brain computer tomography (CT) scan. Then, DNA was extracted from blood cells and exon 4 of the AQP4 gene amplified by the polymerase chain reaction and directly sequenced. On discharge, GOS was assigned by a neurologist blind to the CGS on admission. We did not find any variation in exon 4 of the AQP4 gene in our considerable large sample. Despite this negative result, there is a strong biological rationale for the involvement of AQP4 gene in brain edema regulation and, as consequence, in TBI. Therefore, further studies should be performed, including the assessment of the other three exons of the AQP4 gene.