Objectives: To analyze the factors associated with the non-development of immunogenicity in the adult population vaccinated against HBV. Materials and Methods: A case-control study was performed in a population of patients vaccinated against HBV, who were titrated to antibodies against HBV surface antigen between the years 2015 and 2016. Adults (≥ 18 years) vaccinated against HBV, titrated to anti-HBs < 10 mIU/ml, and who did not present chronic hepatitis B or previous history of HBV infection were defined as cases. The controls were defined with the same characteristics of the cases, the only difference being a titre of anti-HBs ≥ 10 mIU / ml. The factors analyzed were age, sex, number of doses, and some comorbidities such as HIV infection, type 2 diabetes mellitus, and chronic kidney disease on hemodialysis. A bivariate analysis was performed using the Mann-Whitney Chi2 and U tests, as well as a multivariate analysis using binary logistic regression to generate a predictive model. Results: The cohort of patients with anti-HBs titers was composed of 205 participants, which included 39 cases and 166 controls (power: 91%, significance of 0.05). The bivariate analysis showed that the variables age (OR 3.19, p = 0.005), number of vaccine doses (OR 4.82, p = 0.001), hemodialysis CKD (OR 8.85, p = 0.001), Diabetes mellitus 2(OR 4.38, p = 0.001), and the time from onset of vaccination (OR 0.36, p = 0.006), were associated with non-development of seroprotection against HBV. Likewise, age groups ≥ 40 years and ≥ 60 years were highly significant in this analysis, OR 3.19 and OR 8.93, respectively. In the multivariate analysis, only age as a numerical variable (OR:1.05) and number of doses (OR: 2.74), after being adjusted by the other variables, were the only ones that explained the non-development of seroprotection in adults. The final logistic model with the variables indicated explains in 74% the non-seroprotection. Conclusions: Age and number of doses are the only associated variables able to predict with high certainty the non-seroprotective vaccination against HBV.