Infection is a leading cause of mortality in the first years following heart transplantation. We aimed to validate humoral immunity profiles to identify heart recipients at risk of severe infections.We prospectively analyzed 267 adult heart recipients from May 2009 to May 2011 performed at 9 centers in Spain. Study points: before transplantation, 7 and 30 days after transplantation. Immune parameters: IgG, IgM, IgA, complement factors C3 and C4 (nephelometry), anti-pneumococcal polysaccharide (anti-PPS, ELISA-IgG) and anti-cytomegalovirus antibodies (ELISA-IgG). Serum samples were sent to the coordination center for testing. Testing of IgG, C3 and C4 was also performed in some collaborative centers. Clinical follow-up: Over a 6-month period. Clinical outcome: Severe infections requiring IV antimicrobial therapy. Definition of IgG hypogammaglobulinemia (HGG): IgG<600 mg/dL. Statistics: Logistic regression, Pearson correlation.During follow-up 84 (31.5)% of patients developed at least one episode of a severe infectious complication. Before transplantation, the combination of IgG<1100 mg/dL + C3<126 mg/dl (OR 1.96, CI 95% 1.05-3.66, p=0.034) was an immunological risk profile associated with severe infection. At day 7 after transplantation the combination of IgG<700 mg/dl + C3<80 mg/dL + C4<20 mg/dL was more strongly associated with the outcome (OR 5.52, CI 95% 2.27-13.42, p=0.0002) than HGG as a single marker (OR 2.93; CI 95%: 1.57-5.48, p=0.0008). At day 30 IgG<700 + anti-PPS <10 mg/dL (OR 2.63, CI 95% 1.37-5.07, p=0.0038) was more strongly associated with infection risk than HGG (OR 1.92, CI 95% 1.06-3.44, p=0.029). Variability of markers: Correlation between data obtained at the coordination and collaborative centers was as follows: IgG: R=0.89, p<0.001; C3: R=0.59, p<0.001; and C4: R=0.95, p<0.001.In a multicenter study, early immunologic monitoring of humoral immunity profiles was useful to identify heart recipients who are at risk for severe infection.