Nicotinic receptors (nAChRs) have long been investigated as targets for modulation of pain and inflammation. The α7 subtype of nAChR has more recently been demonstrated to have an important role in pain and inflammation. These receptors are expressed widely in neuronal and immune cells, including myeloid lineage cells, which mediate the endogenous cholinergic anti-inflammatory pathway in cultured immune cells. Complete knock-out of α7-nAChRs in mice results in increased inflammation and hyperalgesia, while α7-nAChR gain of function mice experience attenuation of hyperalgesia and inflammation. However, the mechanism of α7-nAChR attenuation of inflammation is not fully understood. We hypothesize that α7-nAChRs expressed on myeloid lineage cells play an important role in nociception and inflammation in vivo. Conditional knock-out mice deficient in α7-nAChR expression in myeloid cells (α7 cKO) and functionally wild-type (WT) mice were generated using Cre-loxP methodology. Acute inflammation was modeled in the mice using a surgical model in which the hind paw was incised and a chemical model in which mice were injected with LPS. Chronic inflammation was modeled using CFA injected in the dorsal hind paw. Evoked thermal hypersensitivity, mechanical hypersensitivity, and paw edema were measured. Pro-inflammatory cytokine expression in the dorsal root ganglia (DRG) and spinal cord after CFA injection was measured using qRT-PCR. In the surgical and chemical acute inflammatory pain model, all mice in the treatment group experienced increased paw withdrawal latency and increased paw edema, but there was no significant difference in thermal or mechanical hyperalgesia or paw diameter between α7 cKO and WT groups. In the chronic inflammatory pain model, however, a greater degree of hyperalgesia and paw edema was seen in α7 cKO mice compared to WT mice. Additionally, expression of pro-inflammatory cytokines IL-1β and TNF-α was increased in the DRG. In the acute inflammatory pain model, the absence of a significant difference between α7 cKO and WT mice indicates that α7-nAChRs in myeloid lineage cells may not play an important role in the modulation of acute inflammation. In contrast, in the chronic inflammatory model, significantly increased hyperalgesia and paw edema of α7 cKO mice suggests that deficiency of α7-nAChRs in myeloid cells contributes to increased inflammatory response. This is further demonstrated by the elevation of pro-inflammatory cytokine expression in the DRG after CFA, indicating that α7-nAChRs in myeloid lineage cells mediate attenuation of chronic inflammation, making them useful targets for the treatment of chronic pain.