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Background. Preterm birth remains one of the most serious problems in obstetrics care globally. In Ethiopia preterm delivery is a direct cause of 28% newborn deaths. However, little is known about the risk factors of preterm birth. Objective. To determine risk factors of preterm birth in Tigray, Ethiopia. Methods. A hospital-based, unmatched case-control study was conducted among 288 respondents (cases=96; controls=192). Data were collected during individual interviews and through a chart review. Statistical analysis included descriptive statistics and bivariate and multivariate binary logistic regression analysis (significance level p<0.05). Results. The response rate was 100%. The mean (standard deviation) age of the respondents was 26.1 (5.9) years. Urban residence (adjusted odds ratio (aOR) 3.11; 95% confidence interval (CI) 1.181 - 8.168)), gynaecological problems (aOR 8.9; 95% CI 1.580 - 50.252), hard physical work during pregnancy (aOR 3.85; 95% CI 1.622 - 9.144), being younger than 18 (aOR 4.56; 95% CI 1.702 - 12.215) and being a first-time mother (aOR 4.66; 95% CI 1.635 - 13.254) were identified as statiscally significant risk factors of preterm delivery. Micronutrient supplementation (aOR 0.26; 95% CI 0.008 - 0.084) and nutritional counselling during pregnancy (aOR 0.24; 95% CI 0.067 - 0.862) were identified as protective factors against preterm birth. Conclusion. The study identified various factors associated with an increased risk of preterm birth and also some protective factors against preterm birth. Programmes to improve maternal and newborn healthcare are recommended to reduce the incidence of preterm births in this region. [ABSTRACT FROM AUTHOR]