Inflammation plays a crucial role in the development and progression of atherosclerotic plaques. The aim of this study is to compare culture supernatants from uncomplicated and complicated carotid atherosclerotic plaques by a multiplex approach, to assess the molecular mediators associated with a complicated plaque phenotype. Atherosclerotic plaques were obtained from 17 patients undergoing carotid endarterectomy. Supernatants from plaque cultures were evaluated by Bio-Plex cytokine assay to determine 27 pro- and anti-inflammatory cytokines, chemokines and growth factors. Complicated plaques secreted higher levels of IP-10 (p = 0.027) and lower levels of IL-5 (p = 0.045) than did uncomplicated ones. Distinctive secretory patterns of cytokines, chemokines and growth factors were present in the two types of plaque. Our study identifies IP-10 and IL-5 as proteins differentiating complicated and uncomplicated plaques from human carotid arteries and provides new insights into the interplay of molecular mediators with atherosclerotic plaque progression.