We previously observed that natural killer (NK) activity toward K562 cells is markedly depressed in patients with beta-thalassaemia major. Here we report that these patients also exhibit significantly decreased (P less than 0.005) NK cytotoxicity against human fibroblasts infected with herpes simplex virus-type 1 (HSV-1) and that the amount of alpha-interferon (alpha-IFN) generated during the latter assays is significantly less than normal (P less than 0.005). This decreased production of alpha-IFN may account in part for the decreased NK activity seen in the thalassaemia patients. On the other hand, the cytotoxicity of their mononuclear cells (MNC) toward both K562 cells and HSV-1-infected fibroblasts could be augmented to the same extent as that of normal MNC by preincubation with alpha-IFN suggesting that thalassaemia MNC are capable of responding to this lymphokine despite their reduced ability to produce it. Moreover, preincubation of thalassaemia MNC with desferrioxamine (DFO), an iron-chelating agent, consistently increased the lysis of K562 cells indicating that the transfusion-induced iron overload which these patients experience may also contribute to the defective NK function seen in this disease. We have now found that preincubation of such MNC with DFO has no effect upon production of alpha-IFN when the MNC are cocultured with either HSV-1-infected fibroblasts or K562 cells. Combining DFO and alpha-IFN resulted in an increase in the NK activity of both normal and thalassaemia MNC against the two targets which was greater than that with alpha-IFN alone. In fact, preincubation of thalassaemia cells with this combination increased their NK activity toward K562 targets to that of untreated normal cells. This was true when either unfractionated MNC or NK-enriched fractions were used as effector cells. These results suggest that DFO and alpha-IFN enhance NK activity by different mechanisms, both of which appear to be reversibly impaired in thalassaemia patients.