Antiretroviral therapy-related dyslipidemia increases the risk of cardiovascular disease (CVD) and is less frequently observed with nevirapine. Whether substituting rilpivirine for nevirapine has dyslipidemic consequences and alters CVD risk is unknown. The aim of this prospective open-label clinical trial was to evaluate serum lipids, cardiovascular risks, and lipid treatment goals over 48 weeks after switching from nevirapine to rilpivirine. Fifty HIV-1-suppressed patients on stable once-daily nevirapine plus emtricitabine/tenofovir-DF were switched to single-tablet rilpivirine/emtricitabine/tenofovir-DF. Lifestyle, weight, systolic blood pressure (SBP), ≥6 h overnight fasting lipids, 10-year Framingham risk scores (FRS), and Adult Treatment Panel III (ATP-III) lipid goals were evaluated over 48 weeks. Patients were 82% males, were a median of 45 years of age, and were on nevirapine for a median of 66 months. Diets, exercise levels, body mass index, and smoking status did not change during follow-up. At week 24, significant changes (p<0.001) were seen in mean [95% confidence interval (CI)] total cholesterol (-0.67 mmol/liter, CI: -0.50 to -0.83), low-density lipoprotein cholesterol (-0.36, CI: -0.21 to -0.51), and high-density lipoprotein cholesterol (-0.28, CI: -0.20 to -0.35). The total cholesterol/high-density lipoprotein cholesterol ratio increased 0.20 (CI: 0.02 to 0.37; p=0.029). Triglycerides did not change and the SBP decreased 6 mmHg (CI: -1.7 to -10.3; p=0.007). Week 48 lipid profiles and SBP were similar to week 24. The median FRS did not change during follow-up (-0.7%, p=0.119). More patients achieved ATP-III low-density lipoprotein cholesterol (+14.9%; p=0.016) and total cholesterol goals (+25.5%; p<0.001). The lipid profile changes after substituting rilpivirine for nevirapine did not significantly influence FRS, although SBP and the ATP-III low-density lipoprotein and total cholesterol goals improved.