Macrophages are key players in both regulatory and inflammatory immune responses. They are implicated in the pathogenesis of rheumatoid arthritis (RA) where they accumulate in the synovium and produce pro-inflammatory cytokines including TNFα and IL-6. The rheumatoid synovium is metabolically distinctive, with low oxygen perfusion and high concentrations of lactate and reactive oxygen species (ROS). Macrophages are known to respond to metabolic signals, therefore we wanted to explore whether metabolic phenotypes of differentiated macrophages could play a role in the persistence of RA. We used an in vitro model of pro-inflammatory “classically activated” and “alternatively activated” macrophages to study macrophage behaviour using metabolomic and transcriptomic techniques. Differentiation with GMCSF and M-CSF produced macrophages with distinctive profiles. GM-CSF macrophages were metabolically active, metabolising glucose, glutamine and fatty acids, while M-CSF macrophages utilised fatty acid β-oxidation alone. Activation of macrophages with LPS, LPS+IFNγ or IL-4 produced metabolic changes, however, differences between MCSF groups were modest. LPS activation of GM-CSF macrophages drove both depletion of intracellular metabolites and transcriptional downregulation. In contrast, IL-4 activation of M-CSF macrophages was metabolically activating. We propose that the metabolic adaptability of GM-CSF macrophages may put them at an energetic advantage in the hypoxic, ROS-enriched rheumatoid synovium.