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Summary: To investigate long COVID-19 syndrome (LCS) pathophysiology, we performed an exploratory study with blood plasma derived from three groups: 1) healthy vaccinated individuals without SARS-CoV-2 exposure; 2) asymptomatic recovered patients at least three months after SARS-CoV-2 infection and; 3) symptomatic patients at least 3 months after SARS-CoV-2 infection with chronic fatigue syndrome or similar symptoms, here designated as patients with long COVID-19 syndrome (LCS). Multiplex cytokine profiling indicated slightly elevated pro-inflammatory cytokine levels in recovered individuals in contrast to patients with LCS. Plasma proteomics demonstrated low levels of acute phase proteins and macrophage-derived secreted proteins in LCS. High levels of anti-inflammatory oxylipins including omega-3 fatty acids in LCS were detected by eicosadomics, whereas targeted metabolic profiling indicated high levels of anti-inflammatory osmolytes taurine and hypaphorine, but low amino acid and triglyceride levels and deregulated acylcarnitines. A model considering alternatively polarized macrophages as a major contributor to these molecular alterations is presented.