Two wood-derived cellulose nanofibril (CNF) porous scaffolds were prepared by TEMPO-oxidation and carboxymethylation. The effects of these scaffolds on the production of inflammatory cytokines by human macrophage-like cells (U937) was profiled in vitro after 1 and 3 days and in subcutaneous tissues of rats after 4 and 30 days, using PCR and Multiplex arrays. Tissue culture plates (TCP) and gelatin scaffolds served as controls in vitro and in vivo respectively. After 3 days in vitro, there was no significant difference between the effects of CNF scaffolds and TCP on the production of chemokines/growth factors and pro-inflammatory cytokines. At day 4 in vivo there was significantly higher gene expression of the anti-inflammatory IL-1Ra in the CNF scaffolds than the gelatin scaffold. Production of IL-1β, IL-6, MCP-1, MIP-1α CXCL-1 and M-CSF was significantly less than in the gelatin, demonstrating an early mild inflammatory response. At day 30, both CNF scaffolds significantly stimulated the production of the anti-inflammatory cytokine IL-10. Unlike gelatin, neither CNF scaffold had degraded 180 days post-implantation. The slow degradation of CNF scaffolds resulted in a foreign body reaction, with high production of IL-1β, IL-2, TNF-α, IFN-ϒ, MCP-1, MIP-1α, M-CSF, VEGF cytokines and expression of MMP-9 gene. The surface chemistry of the CNF scaffolds elicited a modest effect on cytokine production and did not shift the inflammatory profile in vitro or in vivo. The decisive role in development of the foreign body reaction was the slow degradation of the CNF scaffolds.