Objectives: Patients with elevated lipoprotein(a) [Lp(a)] and fibrinogen levels have an increased risk of coronary heart disease and adverse cardiovascular events. There is evidence that coronary plaque progression is linked to a higher risk for future cardiovascular events. Background: There are no data demonstrating a relation between Lp(a), fibrinogen, and directly measured coronary plaque progression over time. Methods: We performed a retrospective analysis of serial intravascular ultrasound (IVUS) studies of 60 left main stems (18 ± 9 months apart) to evaluate plaque progression in relation to Lp(a) and fibrinogen levels and association with adverse cardiovascular events. Results: There was a positive correlation between Lp(a) (r = 0.58; p < 0.0001), fibrinogen (r = 0.48; p < 0.0001), and changes in plaque-plus-media area. Patients with plaque progression (n = 41) had higher Lp(a) (30 ± 26 mg/dl vs. 14 ± 9 mg/dl; p < 0.0012) and fibrinogen (295 ± 88 mg/dl vs. 240 ± 72 mg/dl; p = 0.019) levels than patients with plaque regression (n = 19). Multivariate linear regression analysis showed Log Lp(a) (regression coefficient = 9.45; p = 0.0008) but not fibrinogen to be independently associated with plaque progression. A total of 19 patients suffered from adverse cardiovascular events; they had higher Lp(a) (44 ± 30 mg/dl vs. 16 ± 12 mg/dl; p < 0.0001) and fibrinogen (342 ± 73 mg/dl vs. 248 ± 76 mg/dl; p < 0.0001) levels. Multivariate logistic regression analysis showed Log Lp(a) (odds ratio 10.20, 95% confidence interval 2.36 to 44.13; p = 0.0019) and fibrinogen (odds ratio 1.01, 95% confidence interval 1.00 to 1.03; p = 0.018) were independently associated with adverse cardiovascular events. Conclusions: Serial IVUS showed a positive correlation between Lp(a) and fibrinogen levels and plaque progression. Lp(a), but not fibrinogen, remains independently associated with plaque progression. In addition, the present data suggest a considerable incremental value of Lp(a) in predicting cardiovascular risk.