In this study, differential display technology was used to compare gene expression in cultured fibroblasts from patients with major depression, melancholic subtype vs nonmelancholic depressives and normal volunteer controls, Genes differentially expressed in depressives and normals included an overexpressed 269 bp sequence tag showing ∼95% identity with the Homo sapiens long pentraxin 3 (PTX3) gene sequence in the 3′ noncoding region. The 269 bp complimentary DNA probe hybridized with the 1.9 kb PTX3 mRNA. The densitometric analysis of slot blots showed that the mean steady-state mRNA level of PTX3 was 3.5-fold higher in the melancholic group as compared to that in normal controls and in nonmelancholic depressives (n = 8, all groups). Incubation experiments were then conducted: confluent fibroblasts from melancholics and normal volunteers were incubated with isoproterenol 1 μM, dexamethasone (DEX) 500 nM, and interleukin 1β (IL-1β) 50 ng/ml, for 0, 0.5, 1, 4, and 24 h. mRNA was isolated and quantitated using Northern blot analysis. Isoproterenol produced no significant change in PTX3 expression; DEX produced a significant increase at 4 and 24 h; IL-1β induced an increase in both the groups that peaked at 4 h, declining to near basal levels at 24 h. There were no differences between melancholics or controls in mean change or maximum response with either DEX or IL-1β. The results are consistent with the reported effects of IL-1β on PTX3 expression in mouse brain. The results are of potential importance because PTX3 is a member of the long pentraxin subfamily of acute-phase proteins, which is inducible by IL-1β, and may play roles in neuroimmunity and neuroprotection.