Background: Dialysis is imperative for patients with end-stage renal disease; however, compliance ensures its efficacy. Nursing intervention has been considered to improve compliance. Purpose to examine the effect of designed educational nursing intervention on knowledge and compliance to therapeutic regimen among patients with hemodialysis. Setting: The study was carried out at the hemodialysis unit in Menoufia University and Shebin El-Kom Teaching Hospitals. Sampling: A consecutive sample of 100 adult patients on hemodialysis were selected and divided alternatively into two equal groups: 50 patients for each group (study - control). Instruments: Two instruments were used for data collection: Structured interview questionnaire, and compliance assessment data sheet. Results: It is revealed that pre intervention, mean total knowledge scores were 8.04±3.746 and 8.00±3.714 among study and control groups respectively. While 3 months post intervention, the mean total knowledge scores show higher statistically significant difference in improvement among study group than control group recording 37.32±6.195 and 8.96±4.035 respectively. The minority of study group and control group (14%) comply to therapeutic regimen preintervention that was increased three months post intervention to (86%) among study group compared to control group. Conclusion: Educational nursing intervention was effective in improving compliance and knowledge among patients with hemodialysis. Recommendation: Monthly compliance progress report should be initiated in the hospital by the dialysis nurse to discuss patient's non-adherence behaviors also continuous counseling sessions and motivation should be provided to help patients in complying with therapeutic regimen.