Objective To evaluate the effect of second-line antiretroviral treatment (ART) on human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) and provide reference for subsequent HIV/AIDS treatment.Methods Two hundred and twenty-eight HIV/AIDS patients received second-line ART during January 2011 and December 2015 in Zhengzhou were included.Two hundred and forty-eight who received first-line ART during this period were randomly enrolled as control group.CD4+ T cell count and HIV RNA load before and after treatment were compared with x2 test and t test when appropriate.Results There were 228 patients (137 male and 91 female) in the second-line ART group and 248 patients (176 male and 72 female) in the control group.In second-line ART group, CD4+ T cells increased from (274±200)/μL to (476±261)/μL after an average treatment of (39.5±18.8) months.The difference was statistically significant (t=12.91, P<0.05).In control group, CD4+T cells increased from (251±199)/μL to (470±233)/μL after an average treatment of (35.7±14.7) months.The difference was statistically significant (t=14.60, P<0.05).CD4+ T cells showed no statistical difference between two groups regardless of treatment (t=1.25 and 0.26, respectively, both P>0.05).During the treatment, the rates of immunological failure were 9.6% (22/228) in second-line ART group and 12.9% (32/248) in the control group.There was no statistical difference between two groups (x2=1.251, P>0.05).Complete viral inhibition rates were 83.3% (190/228) in second-line ART group and 88.7% (220/248) in control group with no statistical difference (x2=2.881, P>0.05).Conclusions Second-line ART regimen has equivalent treatment efficacy with first-line ART.To achieve a better outcome, second-line ART regimen should be selected as an alternative option when first-line regimen fails.Compliance is the key to guarantee the success of antiviral therapy.