Background: The nurse has a very important role before, during and after uterotonic drugs administration through assessment, observation, proper interventions and notification of any abnormalities to the physician to render the highest quality of obstetrical care. The aim of this study was to: Evaluate the effect of the instructional guidelines regarding uterotonic drugs administration on nurses' performance and labor outcome. Subjects and Methods: A quasi experimental research design was used. The study was conducted at three settings of labor units in Tanta city: Tanta University Hospital, El-Menshawy General Hospital and El-Mabara Hospital. The sample of this study consisted of all available nurses (40 nurses) as well as a purposive sample of 120 parturient women. Three tools were used for data collection; Tool I, Structured interview schedule, it included two parts. Part (1): Nurses socio-demographic characteristics. Part (2): Assessment of nurses′ knowledge regarding uterotonic drugs. Part (3): Socio-demographic characteristics of parturient women. Tool II: Observational checklist for nurses′ practice regarding uterotonic drugs administration. Tool III: Labor outcome assessment tool. Results: The implementation of the instructional guidelines resulted in a significant positive improvement of nurses' performance regarding uterotonic drugs administration compared to pre instructional guidelines implementation consequently the maternal, fetal and neonatal outcomes were positively improved. Conclusion: it can be concluded from this study that the research hypothesis has been achieved after implementation of the instructional guidelines regarding uterotonic drugs administration which resulted in a statistically significant positive improvement of maternity nurses' performance and labor outcome immediately and three months later compared to pre guidelines implementation. Recommendations: Planning in-service training programs for all nurses must be conducted in order to improve, update and refresh their knowledge and qualify their practices dependent on recent evidence based guidelines regarding uterotonic drugs administration