LINE-1 (L1) retrotransposons represent one of the most successful families of autonomous retroelements, accounting for at least 17% of the human genome. The expression of these elements can be deleterious to a cell. L1 expression has been shown to result in insertional mutagenesis, genomic deletions and rearrangements as well as double-strand DNA breaks. Also, L1 expression has been linked to the induction of apoptosis. These recent discoveries, in addition to correlations of L1 expression with cancer progression, prompted us to further characterize the effect of L1 expression on cellular viability. We show a marked decrease in the overall cellular vitality with expression of the L1 that was primarily dependent on the second open reading frame (ORF2). Both the endonuclease and reverse transcriptase domains of ORF2 can individually contribute to the deleterious effects of L1 expression. L1 decreases cellular viability both by the previously reported apoptotic signaling, but also by inducing a senescence-like state.