Background: Meta-analyses of general population studies report mean low-density lipoprotein cholesterol (LDL-C) reductions of 30% to <50% with moderate-intensity and ≥50% with high-intensity statins. Persons living with human immunodeficiency virus (PLWH) are at high risk for atherosclerotic cardiovascular disease (ASCVD), yet many have elevated LDL-C. Objective: To evaluate LDL-C response after statin initiation among PLWH. Methods: We conducted a retrospective cohort study of PLWH initiating statins between 2009 and 2013 (N = 706). Patients were categorized into mutually exclusive groups in the following hierarchy: history of coronary heart disease (CHD), diabetes, prestatin LDL-C ≥190 mg/dL, 10-year predicted ASCVD risk ≥7.5%, and none of the above (ie, unknown statin indication). The primary outcome was a ≥30% reduction in LDL-C after statin initiation. Results: Among patients initiating statins, 5.8% had a history of CHD, 13.6% had diabetes, 6.2% had LDL-C ≥190 mg/dL, 35.4% had 10-year ASCVD risk ≥7.5%, and 39.0% had an unknown statin indication. Among patients with a history of CHD, 31.7% achieved a ≥30% LDL-C reduction compared with 25.0%, 59.1%, and 33.9% among those with diabetes, LDL-C ≥190 mg/dL, and 10-year ASCVD risk ≥7.5%, respectively. In multivariable adjusted analyses and compared to patients with an unknown statin indication, LDL-C ≥ 190 mg/dL was associated with a prevalence ratio for an LDL-C reduction ≥30% of 1.81 (95% confidence interval, 1.34–2.45), whereas no statistically significant association was present for history of CHD, diabetes, and 10-year ASCVD risk ≥7.5%. Conclusion: A low percentage of PLWH achieved the expected reductions in LDL-C after statin initiation, highlighting an unmet need for ASCVD risk reduction.