Objective To explore the effect of positive psychology intervention based on the positive emotion, engagement, relationships, meaning, achievement (PERMA) theory on the subjective well-being and coping styles of parents of children with severe beta-thalassemia major. Methods A total of 118 parents of children with severe beta-thalassemia major were randomly assigned to a control group or an intervention group, with 59 in each group. The control group was given routine health education and psychological care, while their counterparts in the intervention group received positive psychology intervention based on the PERMA theory for six months. Parents′ subjective well-being and coping style were assessed before and one month after the intervention in both groups. Results The intervention group had significantly higher subjective well-being and positive coping scores, whereas lower negative coping score compared to the control group (all P<0.05). Conclusion Positive psychology intervention based on the PERMA theory can effectively improve subjective well-being of parents of children with severe beta-thalassemia major, thus to help them positively cope with the disease.