Background Klebsiella pneumoniae is a leading cause of sepsis in young infants. We evaluated the association of invasive K. pneumoniae disease (iKPnD) in relation to antigen-specific immunoglobulin G (IgG) and serum bactericidal activity (SBA) to four polysaccharide capsular (K) serotypes and five lipopolysaccharide (O) serotypes, as well as IgG to MrkA, in infants less than 90 days of age. Methods We conducted a retrospective case-control study in Kenyan and South African infants with blood culture-confirmed iKPnD. Serotype-specific antigen IgG concentrations of cases were compared with hospitalised controls without iKPnD. Geometric mean concentrations (GMCs) were estimated, and scaled covariate-adjusted models were used to estimate risk reduction over a grid of antibody concentrations. Results Transplacental transfer of IgG against various K. pneumoniae antigens increased with advancing gestational age. Serum IgG GMCs (expressed in RLU/mL) to disease-causing homotypic K- or O-serotypes were lower in cases compared with controls for anti-K2 (396 [95%CI: 250-628] vs 660 [95%CI: 562-776]), anti-K25 (396 [95%CI: 251-623 ] vs 1170 [95%CI: 988-1385]), anti-K149 (327 [95%CI: 204-521] vs 492 [95%CI: 435-557]); as well as anti-O1{beta},2 IgG (1282 [95%CI: 782-2101] vs 2250 [95%CI:1904-2658]). Furthermore, overall anti-MrkA IgG was lower in cases (945; 95%CI: 757-1179) compared with controls (1610; 95%CI: 1378-1880). SBA titres (expressed as IC50) did not differ between case and controls by K types, but were lower for O1{beta},2{beta} in cases (27; 95%CI: 12-63 vs. 136; 95% CI: 84-221). Conclusion Our findings provide preliminary evidence that low antibodies against three of four K-antigens, O1{beta},2{beta} and MrkA are inversely associated with iKPnD, and should be explored as potential vaccine antigens.