Ninety eight patients with chronic hepatitis B (CHB) admitted to Department of Infectious Diseases, Yongkang First People′s Hospital from January 2017 to June 2018 were randomly divided into two groups. On the basis of entecavir+dicyclool treatment, patients in control group (48 cases) received health education and weekly telephone follow-up from the nurses, while patients in intervention group (50 cases) received health guidance from doctors and psychological counseling and communication from the nurses. All patients were followed up for 8 weeks. The illness perception, negative emotions, quality of life, and medication compliance were evaluated with the Revised Illness Perception Questionnaire (IPQ-R), Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS), SF-36 and Morisky Medication Adherence Scale (MMAS-8) in two groups, respectively. The results showed that, after 8 weeks, the disease identity, serious consequences, treatment control and disease correlation; SAS and SDS scores; physiological function, emotional function, energy and social function were significantly improved in control group( t=2.30, 3.45, 2.35, 2.23, 5.04, 6.03, 2.03, 2.79, 2.02, 2.34, all P<0.05). All dimension of illness perception; SAS and SDS scores; physiological function, physiological function, emotional function, energy, mental health, social function and general health were also improved significantly in intervention group ( t=4.06, 5.44, 6.91, 8.53, 5.65, 8.77, 7.25, 6.06; 12.71, 11.91, 2.27, 2.60, 4.48, 2.82, 3.65, 3.461, 2.82,all P<0.05). And the personal control, disease correlation and emotional expression; SAS and SDS scores; emotional function and mental health in intervention group were better than those in control group ( t=1.49, 2.74, 2.60, 5.02, 5.18, 5.56, 13.72, all P<0.05). In addition, the medication compliance of patients in both groups was significant improved ( Z=5.56, 13.72, all P<0.01), and the improvement was more marked in the intervention group ( Z=3.22, P<0.01). The study indicates that the comprehensive psychotherapy can more significantly improve the degree of illness perception, negative emotions, quality of life and medication compliance in patients with chronic hepatitis B.