Background: Depo-medroxyprogesterone acetate (DMPA) is the most popular, long-acting rnand highly effective contraceptive method in Sub-Saharan Africa including Ethiopia. It has beenrnreported that DMPA influence lipid profile among various populations and ethnic group withrndifferent patterns, similarly associated with an increased risk of coronary heart disease (CHD). rnObjective: The objective of this study was to investigate the effects of use of DMPA on lipidrnprofile (TC, TG, LDL-c, and HDL-c) of women attending family planning unit in Yirgalem rnGeneral Hospital, Yirgalem, Ethiopia. rnMethods: Cross-sectional study design was conducted on 63 healthy women who have beenrnusing DMPA attending the family planning unit and another 63 age-matched healthy controls rnwho are not using any hormonal contraceptives. The study was conducted from February tornNovember 2020 by using structured questionnaire. Fasting blood samples were collected fromrnthe study participants for the estimation of total cholesterol (TC), triglyceride (TG), high-densityrnlipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c) levels. Datarnwas analyzed by descriptive statistics, Studentâ€™s independent t-test and one-way ANOVA usingrnSPSS V. 23. The statistical significance was considered at p < 0.05. rnResults: Serum TC and LDL-c levels in DMPA users were significantly increased compared torncontrols (P=.003 and P =.000, respectively), on the other hand, serum HDL-c level in DMPA rnusers was significantly decreased (P =.000) compared to controls. Serum TG level in DMPArnusers was higher than control group, however, the difference was not statistically significantrn(P=.83). Changes in variables of DMPA users were independent to the duration of use of DMPA. rnConclusions: Use of DMPA significantly increased the serum level of TC, LDL-c, TC/HDL-crnand LDL-c/ HDL-c ratio levels. A significant decrease was found in HDL-c level in the DMPA rnusers. Furthermore, serum TG level of DMPA users was higher compared to controls; however,rnthis difference was not statistically significant. These changes in lipid profiles were independentrnof the duration of use of DMPA.