Uptake of the positron emission tomography (PET) tracer 2-deoxy-2-18F-fluoro-d- glucose (18FFDG) into macrophages is a sensitive marker of inflammation in atherosclerosis. To assess the anti-inflammatory effects of statins, we studied whether atorvastatin therapy reduces aortic 18FFDG uptake in hypercholesterolemic mice deficient in low-density lipoprotein receptor (Ldlr), and expressing only apolipoprotein B-100 (Ldlr−/−Apob100/100). Thirty-six Ldlr−/−Apob100/100 mice were fed a high-fat diet (HFD) for 12 weeks and then allocated to receive a HFD (n = 13), chow diet (Chow, n = 12), or HFD with added atorvastatin (HFD + A, n = 11), for another 12 weeks. In addition to aortic histopathology, 18FFDG uptake was studied in vivo using PET/computed tomography (CT), and ex vivo by gamma counting of excised aorta. Total cholesterol levels were lower in the Chow and HFD + A groups than in the HFD group (10 ± 3.2, 23 ± 4.9 and 34 ± 9.2 mmol/l, respectively), with the Chow group also showing a lower plaque burden and lower numbers of macrophages in the lesions. Compared to the HFD group, 18FFDG uptake in the aorta (normalized for blood) was lower in the Chow group in both in vivo (2.1 ± 0.21 vs. 1.7 ± 0.25, p = 0.018) and ex vivo (5.2 ± 2.3 vs. 2.8 ± 0.87, p = 0.011) analyses, whereas atorvastatin had no effect on uptake (2.1 ± 0.42 in vivo and 3.9 ± 1.8 ex vivo). 18FFDG uptake correlated with plasma total cholesterol levels. Atorvastatin therapy did not show cholesterol-independent effects on inflammation in atherosclerotic lesions in Ldlr−/−Apob100/100 mice, as determined by histology and 18FFDG PET, whereas a cholesterol-lowering diet intervention was effective. •PET tracer 18FFDG is a sensitive marker of atherosclerotic plaque inflammation.•Potential anti-inflammatory effects of interventions were studied by 18FFDG.•Atorvastatin had no effect on plaque inflammation in Ldlr−/−Apob100/100 mice.•Chow diet reduced plasma cholesterol, plaque size and inflammation.•We found no evidence of cholesterol-independent effects on vascular inflammation.