Abstract Importance Cholesterol content in high-density lipoprotein particles (HDL-C) is associated inversely with coronary heart disease (CHD), but findings from Mendelian randomization studies and randomized trials of HDL-C raising drugs have questioned whether this link is causal. However, these analyses do not exclude a causal role for specific HDL sub-fractions of different density, mobility, size and composition. Objective To determine whether sub-components of the HDL pathway exhibit differing relationships with CHD risk. Design In seven longitudinal studies, we used factor analysis to reduce 21 measures of HDL particle size and lipid content to a smaller number of factors representing different components of the HDL pathway. We constructed factor scores and modelled their associations on CHD risk in adjusted Cox regression analyses. We pooled results using random-effects meta-analysis. Setting Seven population-, individual-, occupational- or community-based longitudinal studies in the UK and Finland. Participants 28,597 participants (49% female, mean age 59.6 years) contributed to the analysis. Exposures Sub-components of the HDL pathway, characterized by 21 measures of HDL size and lipid content based on nuclear magnetic resonance spectroscopy. Main Outcomes Incident fatal or non-fatal CHD. Results We identified 4 HDL components with highly replicable across studies; 3 were indices of particle size/composition (extra-large (XL), large (L) and medium/small (MS)), and the other an index of triglycerides (TG) carried in HDL of all sizes. After up to 17 years of follow-up, 4179 incident CHD cases occurred. After adjusting for age, sex, ethnicity, smoking, systolic blood pressure, body mass index, diabetes and LDL-C, higher levels of the XL and MS factors were linked to a reduced risk of CHD (hazard ratio per 1 standard deviation (SD) increase 0.88 [95% CI 0.85, 0.92] and 0.91 [0.87, 0.94]). In contrast, a SD increase in the level of the TG factor was associated with increased risk of CHD (1.10 [1.07, 1.14]). Conclusions and Relevance We found qualitative differences between sub-components of the HDL pathway and the risk of developing CHD. Discovery of the biological determinants of these components, possibly through genetic analysis, will facilitate selection of drug targets and inform trial design. Key Points Question Can investigation of sub-components of the high-density lipoprotein (HDL) pathway, measured through nuclear magnetic resonance spectroscopy, point to specific therapeutic targets for prevention of coronary heart disease (CHD)? Findings Using individual-level data from seven longitudinal studies including 28,597 participants and 4197 CHD events, we identified two components of the HDL pathway that were associated with reduced, and one that was associated with increased, risk of CHD. Meaning These sub-components of the HDL pathway, if causally related to atherogenesis, offer a route to more precise therapeutic targets for prevention of CHD.