Abstract: Objective To explore the characteristics and determinants of natural changes in CD₄⁺ lymphocyte counts among HIV-infected patients without previous antiviral therapy in two districts of Shanghai.Methods A retrospective study was conducted on HIV-infected patients reported from 1987 through May 2013 in two districts of Shanghai, who had received at least twice CD₄⁺ lymphocyte counting tests before antiretroviral treatment (ART).The characteristics of natural changes in CD₄⁺ lymphocyte count and the determinants of significant decrease in count were described.Results A total of 365 patients were included in the study.The monthly rate of CD₄⁺ lymphocyte count changes between the first and the last counting tests had a median of -4.4 (IQR:-11.1~0.2).Among them 263(72.1%) showed remarkable decrease in CD₄⁺ lymphocyte counts and 143 (39.2%) presented a significant decrease (≥ 30%).Multiple logistic regression analysis indicated that the age, the first CD₄⁺ lymphocyte counts and the interval between the first and the last counting tests were significantly associated with the significant decrease of CD₄⁺ lymphocyte counts among HIV-infected patients.Conclusion Natural changes of CD₄⁺ lymphocyte counts were gentle as a whole among untreated patients infected with HIV in central districts of Shanghai and rapid decrease in CD₄⁺ lymphocyte counts among some HIV-infected patients was associated with many factors.It is held that CD₄⁺ lymphocyte count and its changing rate should be regularly monitored so as to estimate the progress of the disease and perform targeted behavior intervention and clinic intervention.