Background/Objectives: Prognostic biomarkers may provide information about the patient's cardiovascular outcomes. However, there are doubts regarding how high-sensitivity C-reactive protein (hs-CRP) impacts patients with congenital heart disease (CHD). The main objective is to evaluate whether high hs-CRP levels predict a worse prognosis in patients with CHD. Methods: Observational and prospective cohort study. Adult CHD patients and controls were matched for age and sex. Results: In total, 434 CHD patients (cases) and 820 controls were studied. The median age in the CHD patients was 30 (18-62) years and 256 (59%) were male. A total of 51%, 30%, and 19% of patients with CHD had mild, moderate, and great complexity defects, respectively. The body mass index [1.07 (1.01-1.13), p = 0.022)], diabetes mellitus [3.57 (1.07-11.97), p = 0.039], high NT-pro-BNP levels [1.00 (1.00-1.01), p = 0.021], and low serum iron concentrations [0.98 (0.97-0.99), p = 0.001] predicted high hs-CRP levels (≥0.3 mg/dL) in patients with CHD. During a follow-up time of 6.81 (1.17-10.46) years, major cardiovascular events (MACE) occurred in 40 CHD patients, showing the Kaplan-Meier test demonstrated a worse outcome among patients with hs-CRP levels above 0.3 mg/dL (p = 0.012). Also, hs-CRP showed statistical significance in the univariate Cox regression survival analysis. However, after adjusting for other variables, this significance was lost and the remaining predictors of MACE were age [HR 1.03 (1.01-1.06), p = 0.001], great complexity defects [HR 2.46 (1.07-5.69), p = 0.035], and an NT pro-BNP cutoff value for heart failure > 125 pg/mL [HR 7.73 (2.54-23.5), p < 0.001]. Conclusions: Hs-CRP obtained statistical significance in the univariate survival analysis. However, this significance was lost in the multivariate analysis in favor of age, CHD complexity, and heart failure.