Particle size, phase, and transition metals have all been implicated in natural and engineered silica-induced respiratory effects, as well as cellular interactions. However, efforts to unambiguously determine their role in the pro-inflammatory mechanism induction have been hampered due to the use of inhomogeneous samples, with incomplete characterization and the use of high cytotoxic doses. Here, engineered micro- and nano- sized silica particles, which are more homogenous in their materials properties and used in a variety of applications, were characterized and compared to natural silica at a realistic dose level. Natural (2 μm) and engineered silica particles (2 μm and 50 nm) were characterized and controlled for size, morphology, phase, iron presence, surface area, and aggregation. A novel lipid peroxidation-dependent pro-inflammatory mechanism due to the influence of iron, particle size, and phase was hypothesized for these particles under a low non-cytotoxic dose closer to a realistic exposure regime. It was observed that at a 1 μg/ml low non-cytotoxic dose of silica the presence or addition of iron, reduction of particle size, and crystalline phase of natural silica significantly increased superoxide (O2.-) and hydrogen peroxide (H2O2) production in the macrophages. This increase in O2.- and H2O2 production, further lead to phosphatidylcholine-specific phospholipase C (PC-PLC) - mediated inflammatory mediator or cytokine production in macrophages via lipid peroxidation and lipid raft disruption (large fraction sub-domains of plasma membrane involved in signal transduction). Addition of an iron chelator abrogated these responses, supporting the role of iron in the hypothesized mechanism. Activation of PC-PLC - induced inflammatory response was determined by using PC-PLC inhibitor, Tricychodecan-9-yl-xanthate, which blocked the inflammatory mediator production. Microscopy studies with cell-particle interaction revealed that particle size also influenced the uptake of silica particles in the macrophages mainly via phagocytosis, since binding and activation of membrane receptors and subsequent internalization is strongly dependent on nanoparticle size. Also, a high cytotoxic dose of 100 μg/ml showed macrophage particle overload for both particle sizes, with macrophage damage possibly leading to catastrophic release of inflammatory mediators that could obfuscate study of the normal inflammatory response, emphasizing the need for studies with realistic exposure doses. In summary, this work demonstrated the role of particle size, iron, and phase in a lipid raft dependent-inflammatory mechanism induced by particles at a realistic exposure dose via PC-PLC. It should lead to a better understanding of the mechanism and important parameters for the particle-induced inflammatory response of the lungs, and therefore, control of the respiratory effects caused by real-life exposure to natural and engineered particles.