Background. Little is known about coronary plaque in human immunodeficiency virus (HIV)-infected women. Methods. Sixty HIV-infected and 30 non-HIV-infected women without symptoms or history of cardiovascular disease were recruited to assess coronary plaque with coronary computed tomographic angiography and immune activation. Data from 102 HIV-infected men and 41 non-HIV-infected male controls were compared. Results. HIV-infected women demonstrated significantly higher percentages of segments with noncalcified plaque (mean ± SD, 74% ± 28% vs 23% ± 39% compared to female control subjects; median [interquartile range], 75% [63%-100%] vs 0% [0%-56%]; P = .007) and more segments with noncalcified plaque (mean ± SD, 0.92 ± 1.48 vs 0.40 ± 1.44; median [interquartile range], 0 [0-2] vs 0 [0-0]; P = .04). Immune activation parameters, including soluble CD163 (sCD163; P = .006), CXCL10 (P = .002), and percentages of CD14+CD16+ monocytes (P = .008), were higher in HIV-infected women than in female control subjects, but no differences were seen in general inflammatory markers. Among HIV-infected women with noncalcified coronary plaque, sCD163 levels were significantly higher than in HIV-infected women without noncalcified plaque (P = .04). In multivariate modeling for sCD163 levels among male and female subjects, significant effects of HIV (P < .0001), age (P = .002), and sex (P = .0002) were seen. Conclusions. Young, asymptomatic, HIV-infected women, demonstrate increased noncalcified coronary plaque and increased immune activation, particularly monocyte activation. Independent effects of sex, HIV status, and aging on immune activation may contribute to cardiovascular disease in this population. Clinical Trials Registration. NCT00455793.