BACKGROUND: Cirrhosis-related cognitive dysfunction can result in car crashes due to impaired navigation skills & slowed reaction times. There is insufficient understanding of the neural basis of this impairment. AIM: Determine feasibility of using an MRI-compatible functional MRI (fMRI) driving simulator and differences in performance of cirrhotics vs controls. METHODS: We recruited cirrhotic outpatients and controls between ages 25–70 years, were current drivers, were candidates for MRI & free of alcohol/drug use. Cirrhotics did not have active HE. All subjects underwent an fMRI-compatible task consisting of simulated driving on a single lane highway. The simulation presented 4 blocks of 4 scenarios (1) straight section (SS) (2) Curved highway without oncoming traffic in the opposite lane (No Traffic) (3) Curved highway with oncoming traffic in the opposite lane (Traffic) and (4) Curved highway with oncoming traffic while responding to a ringing cellphone (Traffic+Distractor), Figure 1a,b. Contrast images between curved sections were created. SS was used as a baseline. Group-analysis was performed for each group using these three contrasts via human connectome project guidelines. RESULTS: Seven cirrhotic patients MELD 7 (6, 11), 4 HCV, 2 Alcohol 1 NASH and five controls completed the study. Controls & cirrhotics had statistically similar age 60 ± 15.5 vs 61.8 ± 10, P = 0.08, and gender (men 50% vs 20%, P = 0.3). Patients and controls had similar driving duration of driving 44 (42, 50) vs 45 (24, 51), P = 0.48. On MRI driving simulation- Mean activations: As the driving task complexity increased from No-traffic to Traffic to Traffic+Distractor states, we observed a shift of increased activation from parietal (precuneus, supramarginal and angular gyri) and visual (lingual gyrus, V1 and V2) to frontal (dorsolateral prefrontal cortex, anterior cingulate cortex), and sub-lobar regions (caudate, putamen, pallidum, insula, and thalamus). This pattern reveals a gradual shift from basic visuo-spatial to complex performance brain regions regardless of control or cirrhosis group. Between-group activations: During both Traffic and Traffic+Distractor conditions, cirrhotic patients showed significantly lower activation than controls in brain regions associated with top-down attentional processing (posterior cingulate cortex), error detection and conflict monitoring (anterior cingulate cortex), attentional resource allocation (paracingulate gyrus), visual attention regulation (superior parietal lobule), inhibitory control (left middle frontal gyrus) and regions associated with regulation of voluntary movement (left pallidum, putamen) (Figure 1c). CONCLUSIONS: Using MRI-compatible driving simulation, patients with cirrhosis demonstrated suppressed attention regulation circuits and sensorimotor control compared to controls, which worsened when distractors such as cellphone use were included. This is likely the neural basis for impaired driving skills in cirrhosis.