The therapeutic potential of rHuIFN-α A/D, a hybrid human IFN molecule with equal activity on murine cells, was studied in experimental and spontaneous metastatic models of a murine colon carcinoma COLON 26. rHuIFN-α A/D inhibited experimental pulmonary metastases of COLON 26 and prolonged the survival of BALB/c mice. Dose scheduling, survival and tumour-cell clearance studies showed that the first 5 days were critical in the inhibition of pulmonary metastases. However, it is unlikely that lung NK cells were involved in the anti-metastatic effect of rHuIFN-α A/D because inhibition of pulmonary metastases and a decrease in radio-labelled tumour-cell survival was seen in BALB/c mice depleted selectively of their NK cells by prior treatment with rabbit antiasialoGM1 serum. Although rHuIFN-α A/D stimulated Nit-cell activity in BALB/c mice, it was ineffective in abrogating the NK suppressant action of rabbit anti-asialoGM1 serum on murine lung NK cells. Thus, IFN may mediate its early antimetastatic effect via a mechanism independent of NK-cell stimulation. IFN also inhibited the development of lung metastases from s.c. COLON 26 tumours in normal, NK-depleted and T-cell-deficient mice.