Borrelia burgdorferi (Bb) is a tick-borne bacterium from the family Spirochaetes that is the causative agent for Lyme disease. These bacteria are notable for their ability to evade host defenses and persist extra-cellularly, even though infection elicits potent innate and adaptive immune responses. We previously demonstrated that host interleukin 10 (IL-10), an anti-inflammatory cytokine important for controlling excess inflammation, plays an important role in suppressing the immune-clearance of Bb. We hypothesize antigen-presenting cells (APCs) such as bone-marrow macrophages (BMM) and dendritic cells (BMDC) produce high-levels of IL-10 immediately upon recognition of Bb and this dysregulated IL-10 level subsequently suppresses the elicitation of pro-inflammatory mediators by the APCs against Bb. We also hypothesize that the production of IL-10 by APCs such as BMMs utilizes signaling pathways that are distinct from Bb-elicited pro-inflammatory mediators. Our results demonstrated that both cultured BMM and BMDCs rapidly produce IL-10 upon Bb-stimulation and this IL-10 suppressed the production of pro-inflammatory cytokines (e.g. IL-12), chemokines, reactive oxygen species, phagocytosis, and surface marker upregulation. Our data also indicate that IL-10 production of by BMMs in response to Bb is dependent on surfaceToll-like receptor 2 (TLR2) yet independent of Bb phagocytosis/internalization. While most Bb-elicited pro-inflammatory mediators are also TLR2-dependent, they require that Bb be internalized. Bb-elicited IL-10 production by BMMs is dependent on signaling pathways involving both phosphotidylinositol-3 kinase (PI3-kinase) and mitogen-activating protein kinase (MAP kinase). On the other hand, the elicitation of most pro-inflammatory responses from BMMs by Bb is independent of both PI3-kinase and MAP kinase. Overall, our findings indicate that Bb stimulates APCs to produce dysregulated IL-10 through unique signaling pathways from those that produce inflammatory mediators and that the amount of IL-10 that are produced are sufficient to suppress many APC immune mechanisms that are critical for controlling bacterial infections. The delineation of these IL-10 specific signaling mechanisms should identify pathways that could be targeted to better control the development of Lyme disease.