Background: Immunization is a lifesaving and cost-effective health intervention which reduces childhood morbidity and mortality. There are still 19.9 millions of children who are unprotected by immunization first one year life. Pentavalent Vaccine is composed of five different vaccines that protect against five major diseases: diphtheria, tetanus, pertussis (whooping cough), hepatitis B and Haemophilus influenza type b. According to the national survey 20% of child was pentavalent dropout in Ethiopia. However, Determinants of this immunization dropout had not studied by community based study. Objective: To identify determinants of pentavalent immunization dropout among children aged 12-23 Months in Amhara Sayint district, North East Ethiopia November 2019. Methods: A community-based unmatched case-control study was conducted in fourteen kebeles of Amhara Sayint District, North East Ethiopia from October 16 to November 10, 2019.A total of 533 mother-child pairs (178 cases and 355 controls) were selected by the stratified multistage sampling technique. Interviewer administrated questionnaire employed to collect the data. Data entry was made with Epi-data version 3.1 and exported to SPSS statistical software version 20 for data analysis. A variable with a P-value of <0.25 in the binary logistic regression analysis was considered to be a candidate variable for multivariable logistic regression analysis. Results: This study showed that mothers who had not PNC care service (AOR= 3.4,95% CI:2.03–5.67),more than 30 minutes traveling time to reach vaccination site (AOR= 2.1,95% CI:1.34–3.35), households not visited by health extension workers at least monthly (AOR= 2.7,95% CI:1.69–4.38),home delivery (AOR= 2.5,95% CI:1.50–4.06), Child had not vaccination cards (AOR= 2.4,95% CI:1.37-4.28), and knowledge on child immunization (AOR= 2.0,95% CI:1.13–3.50) were determinants of pentavalent immunization dropout. Conclusion: According to this study showed that home delivery, had not postnatal care services, more than 30 minutes traveling time to reach vaccination site, households did not visited by Health extension workers, Child had not vaccination cards and poor maternal knowledge on child immunization were determinants of pentavalent immunization dropout. Keywords: Drop-out; pentavalent immunization; Determinants; 12-23 months children; Amhara Sayint, Case-control study