Aims: Low levels of HDL cholesterol have been associated with increased risk of infectious disease morbidity and mortality. Nuclear magnetic resonance (NMR) spectroscopy permits the measurement of HDL particle count and allows further subclassification according to particle size. We tested the hypothesis that low number of different HDL subfractions is associated with increased infectious disease morbidity and mortality. Methods and results: HDL particle counts were measured using NMR spectroscopy in 30 195 individuals aged 22-99 years from the Copenhagen General Population Study. Using multiple-event Cox regression and cause-specific hazard models, we assessed risk of hospitalizations due to infection and infectious disease-related death, from 2003 through 2018. During follow-up, 9303 individuals had one or more infectious disease events, and 1558 experienced infectious disease-related death. In multifactorial adjusted analyses, low number of small and medium HDL particles was associated with increased risk of any infection and infectious disease-related death, whereas low number of large and extra-large HDL particles was not. A very high number of small and medium HDL particles was also associated with increased risk of any infection, but not with infectious disease-related death. For small and medium HDL particles and compared to individuals in the 91-95th percentile, hazard ratios (HRs) in individuals in the lowest percentile were 2.31 (95% confidence interval: 1.75, 3.05) for any infection and 3.23 (2.08, 5.02) for infectious disease-related death. For the highest percentile, corresponding HRs were 1.36 (1.07, 1.74) and 1.06 (0.57, 1.98), respectively. Individuals in the lowest percentile had increased risk of pneumonia (HR: 1.86; 95% confidence interval: 1.30, 2.65), sepsis (2.17; 1.37, 3.35), urinary tract infection (1.76; 1.17, 2.63), skin infection (1.87; 1.24, 2.81), gastroenteritis (1.78; 1.01, 3.16), and other infections (2.57; 1.28, 5.16). Conclusion: Low number of the small HDL particles was associated with increased infectious disease morbidity and mortality.