In this study, the Whole Human Genome 44K DNA microarray assay was used for the first time to obtain gene expression profiles in human peripheral blood lymphocytes 2 h after exposure (in suspension) to 6.78 MeV mean energy α particles from extracellular ²¹¹At. Lymphocytes were exposed to fluences of 0.3–9.6 × 10⁶ α particles/cm² [corresponding to mean absorbed α-particle doses (D_α) of 0.05–1.60 Gy] over 30 min. Significantly modulated expression was identified in 338 early-response genes. Up-regulated expression was evident in 183 early-response genes, while the remaining 155 were down-regulated. Over half of the up-regulated genes and 40% of the down-regulated genes had a known biological process related primarily to cell growth and maintenance and cell communication. Genes associated with cell death were found only in the up-regulated genes and those with development only in the down-regulated genes. Eight selected early-response genes that displayed a sustained up- or down-regulation (CD36, HSPA2, MS4A6A, NFIL3, IL1F9, IRX5, RASL11B and SULT1B1) were further validated in α-particle-irradiated lymphocytes of two human individuals using the TaqMan® RT-qPCR technique. The results confirmed the observed microarray gene expression patterns. The expression modulation profiles of IL1F9, IRX5, RASL11B and SULT1B1 genes demonstrated similar trends in the two individuals studied. However, no significant linear correlation between increasing relative gene expression and the α-particle dose was evident. The results suggest the possibility that a panel of genes that react to α-particle radiation does exist and that they merit further study in a greater number of individuals to determine their possible value regarding α-particle biodosimetry.