Purpose: This study aimed to evaluate the feasibility, safety, and immunological outcomes of low-dose cow’s milk oral immunotherapy (CM OIT) in school-aged children and adolescents with severe, persistent cow’s milk allergy (CMA), a group typically considered at a high risk for OIT. Methods: We conducted a retrospective study involving 12 patients (median age, 11.4 years) with immunoglobulin E (IgE)-mediated CMA, who underwent individualized low-dose CM OIT in the outpatient setting at a single tertiary hospital. Baseline and longitudinal clinical and immunological data, including casein-specific IgE and immunoglobulin G4 (IgG4) levels, were analyzed. Patients were classified as either desensitized or unsuccessful based on treatment outcomes. Results: Of the 12 patients with severe CMA, 6 achieved desensitization up to the target dose, while the remaining 6 discontinued treatment because of intolerance or poor adherence. The desensitized and unsuccessful groups showed no significant differences in baseline age, OIT starting dose, or serum casein-specific IgE level. Immunological evaluation revealed a significantly greater increase in serum casein-specific IgG4 (0.87 vs. -0.37 mg/L, P = 0.004) and a significantly lower natural log-transformed fold change in the IgE/IgG4 ratio (-1.38 vs. 0.44, P = 0.008) in the desensitized group. None of the patients required epinephrine during OIT, and adverse events were generally mild. Conclusion In selected high-risk pediatric populations with severe CMA, outpatient-based low-dose OIT using individualized flexible protocols may provide a relatively safe approach that improves tolerability and adherence. Increased casein-specific IgG4 levels and a reduced casein-specific IgE/IgG4 ratio may serve as valuable biomarkers for treatment response.