Mannose-binding lectin (MBL) is a pattern recognition receptor of the complement system and plays an important role in innate immunity. Whether or not MBL acts as an acute-phase response protein in infection has been an issue of extensive debate, because MBL responses have shown a high degree of heterogeneity. Single nucleotide polymorphisms (SNPs) in the promoter (wild-type Y versus X) and exon 1 (A versus 0) of the MBL2 gene can lead to MBL deficiency. This study investigated the influence of SNPs in the promoter and exon 1 of the MBL2 gene on the acute-phase responsiveness of MBL in 143 patients with community-acquired pneumonia. Acute-phase reactivity was observed only in MBL-sufficient genotypes (YA/YA, XA/YA, XA/XA and YA/0). In patients with wild-type exon 1 genotype A/A, positive acute-phase responses were associated with the presence of the YA haplotype and negative responses with its absence. Genotypes YA/0 and XA/XA produced equal levels of MBL in convalescence. In the acute phase, however, patients with genotype XA/XA displayed negative acute-phase responses more often than those with genotype YA/0. Correlation of MBL and C-reactive protein levels in the acute phase of pneumonia also depended upon the MBL2 genotype. In conclusion, acute-phase responsiveness of MBL was highly dependent upon the MBL2 genotype. These data suggest that heterogeneity in protein responses in the acute phase of disease should always be viewed in the light of possible influences of genetic differences in both structural and regulatory parts of the gene.