The interaction of herpes simplex virus (HSV) with mononuclear phagocytes (MP), i.e. monocytes and macrophages, is of importance for the pathogenesis of HSV infections. MP are known to play a significant role in the cellular defence against infections with HSV, but it has also been shown that HSV-1 affects MP. The infection of these cells at different stages of differentiation has different outcomes, and may result in the alteration of important cellular functions. HSV-1 inhibits the morphological differentiation of human monocytes, and this inhibition occurs in spite of the fact that human monocytes are non-permissive to HSV-1. We have studied the effect of HSV infection of monocytes and macrophages on production of essential cytokines and related this effect to the reproduction of the virus. Blood-derived MP were cultured in vitro and inoculated with HSV at different stages of differentiation. Replication of the virus was measured by infectivity titration, detection of HSV antigens by immunofluorescence and detection of HSV-specific mRNA. In monocytes, no viral replication and no production of late protein was seen. HSV IE gene was transcribed in monocytes from some donors, but not from others. In macrophages, virus replicated, but less efficiently than in fully permissive fibroblast cells. The production of IL-1 beta, IL-6 and TNF-alpha in both non-permissive monocytes and permissive macrophages was assayed both at the transcriptional level, as mRNA, and as protein released from the cells. Production of cytokines by MP was affected by HSV-1. The level of cytokine mRNA and cytokine protein did not correspond for all cytokines, which may suggest that translational regulation and/or cytokine inhibitors are important in the regulation of the cytokine response. The cytokine modulation, both at the transcriptional level and measured as biological activity, was different in monocytes and macrophages, and varied between different donors. Our results indicate a relation between permissiveness and cytokine response in mononuclear phagocytes infected with HSV-1. Such a relation may be of importance to both intrinsic and extrinsic defence mechanisms of MP against HSV-1. Our study also demonstrates that even the functions of non-permissive cells such as blood-derived monocytes may be affected by viral infections.