Background: Nursing Informatics along with growth and development of Health Information Technology (HIT) become a fundamental part of nursing practice. Nurses must to equip with NI competency for providing patients' safety. The study aimed: this study aimed to assess the efficacy of guidance program about staff nurses informatics competencies and its effect on patients' safety. Research design: A quasi-experimental design was utilized. Setting: The study was conducted at El Nasr Specialized Hospital – Universal Health   Insurance (UHI) at Port Said Governorate, Egypt. Subjects: consisted of 50 staff nurses. Tools: Three tools were used in the present study for data collection, I) Nursing Staff Informatics Knowledge Questionnaire, II) Nursing Informatics Competency Assessment Questionnaire (NICAT), III)       Patients' Safety Questionnaire. Results: 24.0% of staff nurses had good knowledge level at pre-program phase regard nursing informatics while it improved to be 82.0% at post program and slightly declined to 78.0% at follow up program. about one third (32%) of staff nurses were competent regard nursing informatics competency at preprogram phase while it increased to be the majority (80% & 84%) at post program and follow up program phases, respectively. Also, 26.0% of staff nurses reported that patients' safety was moderate level at preprogram phase, while it increased to be 82.0% & 86.0 % high level of patients' safety at post program and follow up program phases, respectively. conclusion: There was a highly positive statistically significant correlation between staff nurses' informatics knowledge, competency and their patients' safety levels as preserved by staff nurses at follow up program phases. Recommendations: Conduct competency-based nursing informatics training programs for nursing personnel according to their needs and up to date with new competencies. Develop curricular based competencies about nursing informatics and patient safety.