Fish consumption is associated with reduced risk of cardiovascular disease (CVD), which may be partly mediated by alterations in plasma lipids, such as high-density lipoprotein cholesterol (HDL-C). However, comprehensive analyses of associations between fatty fish consumption and lipoprotein subclass profile are limited and show inconsistent results. Therefore, the aim of the present exploratory study was to investigate the association between fatty fish consumption and lipoprotein subclass particle concentrations and composition, with emphasis on HDL. We performed a comprehensive plasma metabolite profiling in 517 healthy adults, using a targeted high-throughput nuclear magnetic resonance spectroscopy platform. The participants were divided into tertiles based on consumption of fatty fish, reported through a validated food frequency questionnaire. We compared the concentration of metabolites between the participants in the lowest and highest tertiles of fatty fish consumption. We show that high-consumers of fatty fish (>223 g/week, median intake 294 g/week) had higher particle concentrations and content of total lipids, and phospholipids in large and extra-large HDL particles, and higher content of total cholesterol, free cholesterol, cholesteryl esters and triglycerides in large HDL particles, than low-consumers (<107 g/week, median intake 58 g/week). Using fatty fish consumption as a continuous variable, we found that fatty fish consumption was associated with lower levels of the inflammation marker glycoprotein acetyls. In conclusion, high-consumers of fatty fish, seem to have a more favourable HDL-C-related lipoprotein profile and anti-inflammatory phenotype than low-consumers of fatty fish. Thus, these data support the current Norwegian dietary recommendations for fish consumption regarding CVD risk.