Hep G2 and Hep 3B cells, two human hepatoma cell lines, showed decreased thymidine (Thd) incorporation into intracellular acid-insoluble pools when exposed to Wellferon, human lymphoblastoid interferon (IFN). Inhibition was maximal after 48 h treatment with Wellferon and was reversible. Significant inhibition in Wellferon-treated Hep 3B cells was noted at concentrations of 1 IFN unit/ml, which was over 1000-fold less than that required to produce equivalent effects in Hep G2 cells. The decrease in Thd incorporation into acid-insoluble pools was due to both alterations in Thd anabolism and a small but significant decrease in incorporation into DNA with no apparent effect on nucleoside transport. The small but significant Wellferon-induced decrease in Thd incorporation into DNA was reflected in a small but significant decrease in cell proliferation in both cell lines. In addition, Wellferon induced a decrease in the steady-state level of c-myc- and P450-specific RNA transcripts but did not affect the steady-state levels of transforming growth factor-B, fos, N-Ras, or erb-B RNA transcripts. These Wellferon effects, however, did not result in any significant antitumour effects when Hep 3B or Hep G2 cells were grown in athymic nude mice treated intraperitoneally with 8 mu/kg/day Wellferon. Wellferon can induce an antiviral state in both cell lines using Semliki Forest virus and Herpes simplex virus as viral challenges. Taken collectively, these data indicate that Wellferon produces both antiviral and slight but significant antiproliferative effects in Hep G2 and Hep 3B cells, but does not produce significant antitumor effects in vivo using these cell lines in nude mice xenografts.