Sterile α motif and HD domain-containing protein 1 (SAMHD1) is a novel intrinsic restriction factor that inhibits the replication of certain retroviruses and DNA viruses through its deoxynucleoside triphosphate triphosphohydrolase activity. A previous study by our group showed that SAMHD1 restrained hepatitis B virus replication and interferon (IFN)‑α induced SAMHD1 expression in liver cells. However the mechanisms of SAMHD1 upregulation by IFN‑α in liver cells have remained elusive. The present study demonstrated that IFN‑α treatment increased SAMHD1 mRNA levels in SMMC‑7721 cells in a time‑dependent manner. Knockdown of STAT1 inhibited the induction of SAMHD1 expression by IFN‑α in SMMC‑7721 cells. STAT2 silencing also suppressed the induction of SAMHD1 expression by IFN‑α in SMMC‑7721 cells. Furthermore, the induction of SAMHD1 expression in SMMC‑7721 cells by IFN‑α was found to be dependent on IFN‑regulatory factor 9 (IRF9). In conclusion, these results suggested that the interferon‑stimulated gene factor 3 complex, which consists of STAT1, STAT2 and IRF9, is required for the induction of SAMHD1 expression by IFN-α in SMMC-7721 cells.