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Natural cannabinoids may have beneficial effects on various tissues and functions including a positive influence on the immune system and the inflammatory process. The purpose of this study was to investigate the effects of natural cannabinoids on the production of pro-inflammatory cytokines by lipopolysaccharide (LPS)-stimulated whole human blood cells. Levels of the pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured before and after exposure of LPS-stimulated whole blood to different concentrations of Cannabidiol (CBD) or a combination of CBD and Tetrahydrocannabinol (THC) extract. LPS stimulated the production of the pro-inflammatory cytokines. Exposure to both CBD and CBD/THC extracts significantly suppressed cytokine production in a dose-dependent manner. Exposure to cannabinoid concentrations of 50 μg/ml or 100 μg/ml resulted in a near-complete inhibition of cytokine production. This study demonstrates that natural cannabinoids significantly suppress pro-inflammatory cytokine production in LPS-stimulated whole blood in a dose-dependent manner. The use of human whole blood, rather than isolated specific cells or tissues, may closely mimic an in vivo sepsis environment. These findings highlight the role that natural cannabinoids may play in suppressing inflammation and call for additional studies of their use as possible novel therapeutic agents for acute and chronic inflammation.