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Inducible cyclization recombinase (Cre) transgenic mouse strains are powerful tools for cell lineage tracing and tissue-specific knockout experiments. However, low efficiency or leaky expression can be important pitfalls. Here, we compared the efficiency and specificity of two commonly used cholangiocyte-specific Cre drivers, the <i>Opn-iCreER^T2</i> and <i>Ck19-CreER^T</i> drivers, using a tdTomato reporter strain. We found that <i>Opn-iCreER^T2</i> triggered recombination of the tdTomato reporter in 99.9% of all cholangiocytes while <i>Ck19-CreER^T</i> only had 32% recombination efficiency after tamoxifen injection. In the absence of tamoxifen, recombination was also induced in 2% of cholangiocytes for the <i>Opn-iCreER^T2</i> driver and in 13% for the <i>Ck19-CreER^T</i> driver. For both drivers, Cre recombination was highly specific for cholangiocytes since recombination was rare in other liver cell types. Toxic liver injury ectopically activated <i>Opn-iCreER^T2</i> but not <i>Ck19-CreER^T</i> expression in hepatocytes. However, ectopic recombination in hepatocytes could be avoided by applying a three-day long wash-out period between tamoxifen treatment and toxin injection. Therefore, the <i>Opn-iCreER^T2</i> driver is best suited for the generation of mutant bile ducts, while the <i>Ck19-CreER^T</i> driver has near absolute specificity for bile duct cells and is therefore favorable for lineage tracing experiments.