Background: Goiter is the abnormal enlargement of the thyroid gland. It has been shown that prevalence of goiter was considerably highest in South Ethiopia particularly in Gamogofa zone. The study was aimed to identify factors that determine goiter among Botre Elementary and Junior Secondary school students, Gamogofa zone, Southern Ethiopia. Methods: Case control study was conducted among Botre Elementary and Junior Secondary School students from February to March, 2014. A total of 298 students; 99 cases and 199 controls, were enrolled in the study. Examination of goiter was performed by Inspection and Palpation techniques. Structured interview guided questionnaire was used to collect data on independent variables. Data were entered using EPI info version 3.5.3 statistical software and analyzed using SPSS version 20 statistical package. Descriptive statistics was used to describe the study population in relation to relevant variables. Bivariate and multivariate logistic regression was also carried out to identify factors that determine the dependent variable. Result: A total of 99 cases and 199 controls participated in the study. Being female [AOR: 2.48, 95% CI: 1.38, 4.44], rural residence [AOR: 2.07, 95% CI: 1.11, 3.86], cassava consumption [AOR: 2.92, 95% CI: 1.52, 5.62], cabbage consumption [AOR: 2.46, 95% CI: 1.17, 5.13], use of other than tap water source for drinking [AOR: 3.76, 95% CI: 2.07, 6.85], and lack of knowledge by parents about prevention of iodine deficiency disorders [AOR: 2.10, 95% CI: 1.03, 4.27] were independent predictors of goiter. Conclusion: More than half of cases use other than tap water source(s) for drinking; either spring, well, river or some form of combination; alone or in addition to tap; which was the strongest independent predictor of goiter. So, access to safe drinking water should be improved for rural residents to reduce the level of goiter and its consequences.