The possibility that nanomaterials could perturb the normal course of an inflammatory response is a key issue when assessing nanoimmunosafety. The alteration of the normal progress of an inflammatory response may have pathological consequences, since inflammation is a major defensive mechanism and its efficiency maintains the body’s health. The immunosafety of engineered nanoparticles at nontoxic concentrations was investigated with the use of a human primary monocyte-based in vitro system, which reproduces in a simplified fashion the full course of the physiological inflammatory response, from initiation and development to resolution. The kinetics of expression and production of inflammatory and anti-inflammatory cytokines and the proteomic profiles were used for describing the inflammatory defensive response. We assessed the ability of gold and silver nanoparticles to trigger inflammation and to interfere with the course of an ongoing defensive reaction. While neither nanoparticle type was able to directly activate monocytes, silver nanoparticles could exacerbate the inflammatory response of monocytes but did not interfere with the resolution of the inflammatory reaction. These findings support the use of human primary monocyte-based in vitro assays for realistically investigating the effects of engineered nanoparticles on human innate immune responses, in order to predict the immunological risk of nanomaterials and implement safe nanoparticle-based applications.