Background: With the advent of antiretroviral treatment, HIV related morbidity and mortality have tremendously decreased. However, some HIV patients on ART don’t optimally respond to the ART regimen to restore the immunity. This study was aimed to determine the pattern of CD4+ T cell recovery and determinants of HIV infected individuals receiving the ART in Mekelle Hospital, Tigray northern Ethiopia. Methods: A hospital based retrospective cross-sectional study was conducted from January, 2010 to August, July 2020 among HIV positive individuals on ART follow up. Data were collected using pre-tested structured questionnaire by trained data collector. Statistical analysis was performed using SPSS V. 20. Bivariate and multivariate analyses were performed to identify the possible predictors for immune reconstitution after ART administration. P-values < 0.05 was considered statistically significant. Results: Of the total 424 study participants, 248(58%) were females. The mean age of the study participants was 37+9 (mean + sd). The median time of ART follow up was 60 (IQR: 36-84) months and the recent median CD4+ T-cell count was 388 (IQR; 254-527) cells/µl. The CD4 cell count increment compared to pre-ART was 166 cells/µl of blood. Age ranges 25-34 years (AOR 2.62, 95%CI: 0.82-8.35), CD4+ T-cell count >200 cells/µl at baseline (AOR 3.53, 95%CI: 2.23-5.58), duration of ART follow up at 12, 48 and 49 and above months respectively (AOR 8.053, 95%CI:1.45-44.84; 4.82, 95%CI:1.16-20.11); and (AOR 6.36, 95%CI:1.63-24.77), and TDF-3CT-Efv ART regimen combination (AOR 2.29, 95%CI:1.32-3.97) were found predictors significantly associated with CD4+ T-cell recovery after long term ART uptake, which characterized by >350 cells/µl increments. Conclusions: The immune restoration of HIV positive individuals depends on the length of ART follow up time and CD4+ T-cell level during the initiation. Moreover, individuals who were taking TDF-3CT-Efv ART drug combination demonstrated a rapid CD4+ T-cell restoration than these who were taking other ART drug regimens.