The value of clinical cluster nursing in the prevention of multi-drug resistant (MDR) infection in patients with severe encephalopathy in ICU was evaluated. ICU patients (n=129) diagnosed with severe encephalopathy between 2012 and 2014 were selected as the study group, while 106 cases of ICU patients diagnosed with severe encephalopathy between 2010 and 2012 were retrospectively selected as the control group. Control group patients were offered conventional integrated nursing care, while the study group patients were offered cluster nursing care. The differences in infection rate, colony and quantity, infection time, number, mortality rate and hospital stays between the two groups were compared and analyzed. Observations on the infection rate, diagnosis time, total number of infection, mortality rate caused by infection and hospital stays were lower in the study group patients than in controls (P<0.05). The patients in the study group had a much lower drug-resistant infection rate than that in the control group (P<0.05). In the patient groups there were infections with methicillin-resistant Staphylococcus aureus , Pseudomonas aeruginosa , Klebsiella pneumoniae and Escherichia coli , although the quantities of the above pathogenic microbe colonies in the study group were notably less than those in the control group (P<0.05). In conclusion, cluster nursing care effectively prevents MDR infections of ICU patients with severe encephalopathy and reduces the mortality rate, thus having an excellent clinical significance.