This study aimed to map quantitative trait loci (QTL) for traits related to humoral innate immune defence. Therefore, haemolytic complement activity in the alternative and the classical pathway, serum concentration of C3c and of haptoglobin (HP) were measured in blood samples obtained from F2 piglets (n = 457) of a porcine F2 resource population before and after Mycoplasma hyopneumoniae, Aujeszky's disease virus (Suid herpesvirus I, SuHVI) and porcine reproductive and respiratory syndrome virus (PRRSV) vaccination at 6, 14 and 16 weeks of age. Animals were genotyped at 88 autosomal markers. QTL analysis was performed under the line cross and the half sib. Phenotypic data were adjusted for systematic effects by mixed models with and without repeated measures statement. In total, 46 and 21 estimated QTL positions were detected with genome-wide significance at the 0.05 and 0.01 level, respectively. The proximal region of SSC2 (orthologous to HSA11 0–70 Mb), the distal region of SSC4 (HSA1 95–155 Mb), and the intermediate region of SSC16 (HSA5 0–73 Mb and 150–174 Mb) showed a clustering of estimated QTL positions for complement activity based on the different models. A common genetic background, i.e. a single true QTL, might underlie these QTL positions for related traits. In addition, QTL for antibody titres were detected on SSC1, 2, 6 and 7. With regard to number and magnitude of their impact, QTL for humoral innate immune traits behave like those for other quantitative traits. Discovery of such QTL facilitates the identification of candidate genes for disease resistance and immune competence that are applicable in selective breeding and further research towards improving therapeutic and prophylactic measures.