Pulmonary macrophages (MØs) are essential for clearance of inhaled particles, innate immunity, and lung tissue maintenance. However, the products of activated MØs have also been implicated in inflammation and tissue destruction, including in chronic obstructive pulmonary disease (COPD). Primary human alveolar macrophages (AMs) are available in limited numbers via bronchoalveolar lavage (BAL) or sputum induction, and BAL macrophages are not commonly available to all researchers. A readily available, plentiful, but representative surrogate for AMs would advance understanding of the contribution of macrophages to lung pathophysiology. Herein the authors describe a method for the in vitro derivation of AM-like cells using primary human peripheral blood monocytes differentiated in suspension with granulocyte-macrophage colony-stimulating factor (GM-CSF). The method produces a cell population with a consistent and stable phenotype. Flow cytometry reveals that GM-CSF-derived macrophages (GM-MØs) express lineage markers, immunoglobulin gamma (Fc gamma) receptors, adhesion molecules, antigen presentation coreceptors, and scavenger receptors akin to AMs. Functionally, cigarette smoke activates extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinase, enhances interleukin 8 (IL8) production from GM-MØs and inhibits phagocytosis, phenotypes previously described for smokers' AMs. Global transcriptional profiling revealed significant overlap in regulated genes between smokers' AMs and GM-MØs treated with cigarette smoke preparations in vitro.