Background: Acceptance of patients with chronic renal failure (CRF) undergoing hemodialysis is different. Acceptance will affect the physical and psychological health of patients and can improve their quality of life and psychosocial adaptation. Acceptance can be influenced by knowledge, perseverance or enthusiasm, means or resources, long diagnosed and spiritual level. Objective: To determine the relationship between the spiritual level and the level of knowledge towards the acceptance of CRF patients undergoing hemodialysis. Method: Quantitative research (correlation/observation analytic) with cross sectional approach. The total sample was 101 respondents. Data collection used the Daily Spiritual Experience Scale (DSES) questionnaire, knowledge of hemodialysis, and Illness Cognition Questionnaire (ICQ) validated and reliable. Data analysis using Spearman correlation test and multiple linear regression test. Results: There is a significant relationship between the spiritual level and the level of knowledge on the acceptance of CRF patients undergoing hemodialysis with p-value 0.000. Linear multiple regression analysis shows the spiritual level has more influence on acceptance than other factors with a beta value of 0.550. Conclusion: The spiritual level and level of knowledge have a significant relationship to the acceptance of CRF patients undergoing hemodialysis. The most influential factor towards acceptance is the spiritual level. Dialysis nurses are advised to continue improve their ability to provide spiritual nursing care to patients undergoing hemodialysis.