Histamine, an endogenous amine is implicated in hypersensitivity (allergic) responses, gastric acid secretion, neurotransmission, immuno-modulation, cell differentiation, and embryonic development. It exerts its effects via four histamine receptor subtypes, termed H to H receptors (HR-HR) belonging to the superfamily of G-protein coupled receptors. The latest discovered histamine receptor, HR, is implicated in the chemotaxis of several cell types and strongly associated with immune and inflammatory responses. Thus, we found interesting to analyze in terms of 2D-QSAR a number of H antagonists in order to highlight the most important physicochemical properties implicated in their mechanism of action and in continuation to suggest structural modifications. The C-QSAR platform of Biobyte has been used in this study. The study reveals that lipophilicity, clog P (linear or bilinear model) as well as steric factors such as the overall molar refractivity (CMR), molar volume or the substitutents molar refractivity (linear) or the sterimol parameters B and B are important. Electronic effects appear only in one model. The study shows that log P as calculated from the C-QSAR program of Biobyte is suitable for this form of QSAR study.