Background: Systemic lupus erythematosus is one of the most common autoimmune diseases in children caused by highly abnormal immune systems and accompanied by extreme morbidity and mortality rate and poor quality of life. Aims: This study aimed to evaluate the effect of instructional guidelines on caregivers to improve quality of life for their children with systemic lupus erythematosus. Research design: A quasi-experimental research design used (one group pre/posttest). Setting: This study was conducted at allergy and immunity out-patient clinic in pediatric hospital affiliated to Ain Shams university hospitals. Subjects: A purposive sample composed of 120 care-givers (mainly mothers) accompanying their children’s with systematic lupus erythematosus at the previously mentioned setting. Tools of data collection: Four tools were used included; a structured interviewing questionnaire, lupus awareness's quizzed, lupus quality of life scale, and structured observational checklist. Results: This study noted that, there was a highly statistically significant difference in relation to the total quality of life of the studied children pre and post implementation of instructional guidelines program with P<0.001. Also, there was a highly statistically positive correlation between total mothers knowledge, reported practices, and quality of life with p<0.001 pre and post program implementation. Conclusion: The current study concluded that, the implementation of instructional guidelines on caregivers affect positively on quality of life for their children with systemic lupus erythematosus. Recommendations: Continuous instructional guidelines program for mothers having children with systemic lupus erythematosus to increase their knowledge and practices regarding care of their children to improve their quality of life.