BACKGROUND: CD4 count is a standard measure of immunodeficiency in adults infected with HIV to initiate and monitor highly active antiretroviral therapy; however, it may not be feasible in resource poor countries. There is a need to have another marker of immunodeficiency that is less resource demanding. OBJECTIVE: The objective of this study was to assess the relationship between total lymphocyte count and CD4 count in one of the resource poor countries, Ethiopia. METHODS: This was a retrospective evaluation. A total of 2019 cases with total lymphocyte and CD4 counts from three hospitals (Yirgalem, Hossana and Arba-Minch) were included in the study. Pearson correlation, linear regression and Receiver Operating Characteristic (ROC) were used. RESULT: For adults, the sensitivity, specificity, positive and negative predictive values of TLC < 1200 cells/mm3 to predict CD4 count < 200 cells/mm3 were 41%, 83.5%, 87.9% and 32.5%, respectively. For subjects aged less than 18 years, these values were 20.2%, 87%, 82% and 27.1%, respectively. A TLC </= 1780 cells/mm3 was found to have maximal sensitivity (61%) and specificity (62%) for predicting a CD4 cell count of < 200 cells/mm3. Meanwhile, a TLC </= 1885 cells/mm3 would identify only 59% of patients with CD4 count of < 350 cells/mm3(sensitivity, 59%; and specificity, 61%). The combined sensitivity and specificity for patients above 40 years of age was greater. CONCLUSION: Our data revealed low sensitivity and specificity of TLC as a surrogate measure for CD4 count.