It has been suggested that the ability to drive a car is impaired in patients with cirrhosis of the liver and minimal hepatic encephalopathy (MHE). However, the only study using an on-road driving test did not reveal such an impairment. In a prospective controlled study, we evaluated patients with cirrhosis of the liver for MHE and the ability to drive a car. MHE was diagnosed using three psychometric tests: Number Connection Test Part A, Digit Symbol Test, and a Complex Choice Reaction Test. In a standardized on-road driving test (22 miles, 90 minutes), designed for patients with brain impairment, a professional driving instructor blind to the subjects' diagnosis and test results assessed the driving performance. Four global driving categories (car handling, adaptation to traffic situation, cautiousness, maneuvering), 17 specific driving actions (e.g., changing lanes, overtaking, etc.), and a total score of driving performance were rated using a 6-point scale. Of 274 consecutive patients with liver cirrhosis, 48 fulfilled the medical and driving inclusion criteria, 14 of them with and 34 without MHE. Forty-nine subjects in a stable phase of chronic gastroenterological diseases and with normal liver findings served as controls. The total driving score of patients with MHE was significantly reduced in comparison to either cirrhotic patients without MHE or to controls (P < .05). Significant differences in ratings were found in the following driving categories: car handling, adaptation, and cautiousness. Significant differences were also found in specific driving actions. The instructor had to intervene in the driving of 5 of the 14 MHE patients to avoid an accident, significantly more than in cirrhotic patients without MHE and in controls. There was no significant difference in any driving category or specific driving action in cirrhotic patients without MHE compared to controls. In conclusion, fitness to drive a car can be impaired in patients with MHE. Therefore, patients with liver cirrhosis should be tested for MHE and informed in the case of abnormal test results. Therapy known to improve psychometric test results should be initiated.