Background: Dyslipidemia represent significant health care concerns in Human immune deficiency virus (HIV) infected patients taking highly active antiretroviral therapy due to their association with cardiovascular disease risk. There is limited data regarding the effects of boosted atazanavir (ATV/r) treatment in the lipid profiles of Ethiopian HIV patients. Thus, this study compares the lipid profile changes of HIV patients on ATV/r-based regimen compared to efavirenz (EFV)-based regimen, while the background nucleos/tide backbone is optimized.Materials and methods: A comparative Hospital based cross-sectional study was conducted among adult HIV-infected patients at Zewditu Memorial Hospital, Addis Ababa, Ethiopia, from July-September 2017. Equal number of EFV and ATV/r-treated patients (n = 90 each) taking for one year and above were included in the study. Serum lipid parameters (triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C)) were measured using fully automated mind ray, Chemistry analyzer. Data comparison used chi-square test, Student t-test and Mann-Whitney U test. Multivariate regression analysis and p-value<0.05 was used to identify associated factors of serum lipid profiles.Results: In the present study ATV/r-treated group resulted significantly higher in the median values of TG [207 (56-1094) vs. 145(42-768) mg/dL; p=0.001] and the mean value of TG/HDL-C ratio (6.6 vs. 4.4; p=0.001) as compared to EFV-treated group. EFV-treated group showed significantly higher in the mean value of HDL-C (44.7 vs. 38.7mg/dL; p= 0.001) as compared to ATV/r-treated group. No significant difference was found in TC (p=0.5), LDL-C (p=0.6), TC/HDL-C (p=0.5) and LDL-C/HDL-C (p=0.1) between EFV and ATV/r-treated patients. In ATV/r-treated patients, CD4 count and body mass index (BMI) was significantly associated with TC. In EFV-treated patients, BMI was significantly associated with increased serum LDL-C and TC in female participants.Conclusion: In conclusion, ATV/r raises TG and TG/HDL-C while, HDL-C was higher in EFV than ATV/r-treated group. Both groups have less atherogenic lipid profiles in terms of TC/HDL-C and LDL/HDL-C.