Background: Patients post thyroidectomy might fail to reach normal levels of Thyroid Stimulating Hormone (TSH). Compliance to lifelong hormonal replacement therapy is greatly necessary to prevent deficiency of thyroid hormone and complications as hypothyroidism. Aim: the study aimed to identify compliance of post thyroidectomy patients to thyroid replacement therapy. Setting: The study was conducted at the endocrine outpatient clinic of the Main University Hospital, Alexandria University, Egypt. Materials and method: A descriptive research design was utilized  . Data was collected from 100 adult patients post thyroidectomy for at least 6 months . Tools: Bio-socio-demographic data structured interview schedule, post thyroidectomy signs and symptoms of hypothyroidism observational checklist, medication compliance questionnaire and factors associated with compliance of patients' to thyroid replacement medication structured questionnaire are tools were utilized for data collection. Results: More than half of the studied patients had low level of compliance. They had signs of hypothyroidism such as dyspnea, hypotension, anorexia and weight gain , all these signs were significantly associated with low level of compliance to therapy where p = (<0.001, 0.002,  <0.001 and <0.001) respectively. Statistically significant relations were found between low level of compliance to replacement therapy and several associated factors such as patients did not know how to read or understand what is written on the medication labels, did not understand why they need to take this medication, and they just forgot where p = (<0.001, <0.001, and <0.001) respectively. Conclusion: Identification of patients' compliance to thyroid replacement therapy and its associated factors is highly needed to achieve appropriate lifelong health outcomes. Recommendation: Replication of the study on large sampling.