Whereas large T antigen (LT) of simian virus 40 (SV40) promotes oncogenesis by inactivating the tumor suppressor proteins p53 and pRb, SV40 small T antigen (ST) has been thought to be dispensable for this process. However, here we show that LT promotes both oncogenic growth and senescence in human cells expressing oncogenic Ras and that this latter effect is antagonized by ST. Inactivation of p53 by LT alone promoted the senescence-associated secretory phenotype (SASP), whereas the additional expression of ST attenuated this phenotype, allowing cells to avoid oncogene-induced senescence (OIS) and thereby promoting efficient oncogenesis. ST interacts with and inhibits the function of heterochromatin protein 1-binding protein 3 (HP1BP3), a positive regulator of global microRNA biogenesis, and it thereby triggers aberrant upregulation of B-cell translocation gene 2 (BTG2), which is essential for prevention of SASP and OIS by ST. Collectively, our results indicate that the HP1BP3-BTG2 axis constitutes a fail-safe system to prevent oncogenesis by means of OIS induction, and that this system is hijacked by ST.