Posterior reversible encephalopathy syndrome (PRES) is a neurologic disorder with multiple etiologies. The signs and symptoms of PRES are non-specific, making the differential diagnosis broad. Although PRES is suspected clinically, a diagnosis requires characteristic findings on imaging. In patients with undiagnosed PRES, the coexistence of substance abuse can divert the care provider from pursuing imaging studies, leading to a missed diagnosis. We describe the case of a 51-year-old male who presented with altered mental status and was diagnosed with PRES despite having a positive urine drug screen.