Background: Stroke is a chronic non-communicable disease results from infraction or spontaneous hemorrhage in the brain. The burden of stroke is increasing in alarming rate globally. In 2013 there were 6.5 million stroke deaths, 113 million disability-adjusted life years due to stroke from this, 75.2% of all stroke mortality and 81.0% of stroke-related disability- adjusted life years are from the developing countries. In Ethiopia, 7% of total deaths are attributed by stroke. This study aims to assess the determinants of stroke among patients with hypertension in Ayder Comprehensive Specialized Hospital, Mekelle, Tigray, Ethiopia, in 2018. Methods: Hospital-based case-control study was conducted from February to April 2018. Cases were adult hypertensive patients with stroke and controls were adult hypertensive patients without stroke. Using a systematic random sampling technique 89 case and 356 controls were included in this study. Record review, physical measurement and interview techniques were used to collect data. Data was entered and analyzed by using SPSS version 23. Variables with a p-value less than 0.25 in bivariate logistic regression were selected for multivariable logistic regression. The adjusted odds ratio and 95% confidence interval were used to determine the association. P-value <0.05 was used to declare statistical significance in multivariable analysis. Result: The mean age of cases were 56.3years (SD±13.53years) and 51.9 years (SD±12.67 years) for controls. Majority 59 (66.3%) of the case and around one third 106(30%) of controls were non-adherent to medication. Lost to follow up (AOR=2.474, 95%CI: 1.368-4.929), alcohol drinking (AOR=2.440, 95%CI: 1.291-4.613), use of salty diet (AOR=3.249, 95%CI: (1.544-6.837), medication non-adherence (AOR=3.967, 95%CI: 2.256-6.973), uncontrolled systolic blood pressure, (AOR=3.196, 95%CI: 1.60-6.382), uncontrolled diastolic blood pressure (AOR=2.204, 95%CI: 1.130-4.297) and high cholesterol level(AOR=2.413, 95%CI: 1.319-4.414) were found to be significant determinants. Conclusion: Alcohol consumption, lost to follow up, salty diet, high cholesterol level and uncontrolled systolic and diastolic blood pressure were significantly associated with stroke so, health education on lifestyle practices and hypertension-related complications in each follow-up visit through health professionals are very essential to avert the problem. Keywords: Stroke, Hypertension, determinant, Mekelle, Ethiopia