<b><i>Introduction:</i></b> Alloimmunization is caused by exposure to erythrocytes from a donor that expresses blood group antigens other than those of the recipient and is related to processes that alter the balance of the immune system. Knowing the pathophysiology of alloimmunization process is essential to understand clinical complications associated with this process. <b><i>Patients and Methods:</i></b> From October 2016 to April 2017, irregular antibody screening was performed in 1,434 polytransfused (compatible with the ABO and D system) patients by means of agglutination techniques using erythrocytes of a known phenotype of 44 patients with a positive alloantibody screening. Non-alloimmunized (control) subjects were matched for age, gender, pathology, and treatment group with alloimmunized patients. The subsets of B, T, and Treg lymphocytes were determined by flow cytometry. <b><i>Results:</i></b> The results of screening for alloantibodies in patients by specificity of antibodies were as follows: nonspecific (30%), followed by anti-Di^a (13%), anti-e (9%), anti-S (9%), anti-I (7%), anti-K (7%), and anti-P (7%). A lower percentage of CD4+ T lymphocytes and an increase of CD8+ T lymphocytes were observed in alloimmunized patients, as well as a low CD4/CD8 ratio (0.7 vs. 1.6, <i>p</i> = 0.003), a higher percentage of B lymphocytes versus the control group (30 vs. 20%, <i>p</i> = 0.003), and a decrease of Treg CD4+ lymphocytes versus the control group (3 vs. 12 cells/μL, <i>p</i> = 0.043). These observations suggest that alloimmunized patients have important alterations in the number of some lymphocyte subsets that can be translated into clinical immune dysregulation. <b><i>Conclusion:</i></b> A decreased CD4/CD8 ratio, increased B lymphocytes, and Treg lymphocyte deficiency are the most significant changes observed in alloimmunized patients.