Abstract We report a case of a 17-year-old girl with a history of congenital human immunodeficiency virus (HIV) infection and lipodystrophy secondary to highly active antiretroviral therapy (HAART). She developed severe worsening of preexisting hypertriglyceridemia after treatment with oral contraceptive pills (OCP) for polycystic ovary syndrome. Her hypertriglyceridemia improved upon OCP discontinuation. Although it is known that estrogen combined with progestins have a negative effect on triglycerides and high-density lipoprotein (HDL) cholesterol levels, to our knowledge the association of HAART-related lipodystrophy and severe hypertriglyceridemia after OCP use has not been reported in the literature. We recommend avoiding the use of OCPs in patients with lipodystrophy due to the increased risk of worsening hypertriglyceridemia.