Introduction (Objectives): This study aimed to evaluate the serological response to a fourth dose of mRNA COVID-19 vaccine in patients with conditions that confer a high risk of severe disease, particularly those with high-level immunosuppression. Methods: An observational study was conducted at the Ramón y Cajal University Hospital between February and August 2022. Adults (≥18 years) with high-risk conditions who had received four doses of either BNT162b2 or mRNA-1273 were included. Anti-spike IgG levels were measured ≥14 days post-vaccination. An adequate response was defined as an antibody concentration ≥260 BAU/mL. Results: A total of 943 patients were analyzed; 846 (89.7%) achieved an adequate response. In the bivariate analysis, patients aged 60–74 years had a higher risk of inadequate response compared to those aged 18–39 years (OR 1.824 vs. OR 0.257). Female sex was associated with a higher risk of inadequate response (OR 1.522; 95% CI: 0.974–2.371). In multivariable logistic regression, patients with high immunosuppression had a higher, though not statistically significant, risk of inadequate response compared with those without. Discussion: Our findings are consistent with international evidence suggesting that age and certain clinical factors reduce vaccine immunogenicity. The observed paradoxical effect of sex could reflect the higher prevalence of aggressive immunosuppressive therapies among women in the study cohort. Conclusions: Most immunosuppressed patients achieved seroconversion after the fourth dose. These results underscore the need for tailored vaccination strategies and additional measures in highly immunosuppressed subgroups.