The Integrator complex plays a critical role in the promoter-proximal termination of RNA Polymerase II-driven transcription through its endonuclease and phosphatase enzymatic activities. INTS6 is a subunit of the Integrator phosphatase module and its loss confers resistance to CDK9 inhibition. To gain deeper insights into the role of INTS6, we generated an endogenous knock-in eHAP1 degron-tagged line. We performed a genome-wide CRISPR knock-out screen in this background using a custom-made library. The screen revealed that INTS6 and its paralogue INTS6-Like (INTS6L) have redundant functions that are essential for cell viability. Interestingly, analogous CRISPR-screens performed in the presence of a CDK9 inhibitor showed the lack of ability of INTS6L to antagonize CDK9 activity, even in absence of INTS6. These apparently conflicting pieces of information suggest that while there are some overlapping functions of INTS6 and INTS6L they also have non-redundant roles. Immunoprecipitation-mass spectrometry (IP-MS) and immunoblotting demonstrated that INTS6L interacts with other members of Integrator, suggesting a possible role of INTS6L in this complex replacing INTS6. In line with this hypothesis, INTS6 and INTS6L proteins are highly similar and have evolutionary conserved domains, except for a deletion in INTS6L that only arose in birds and mammals. We then generated a double degron-tagged line for INTS6 and INTS6L allowing specific and rapid degradation of the proteins. RNA-seq analysis showed that the depletion of both INTS6 and INTS6L has much greater effect on gene expression than INTS6 alone. Taken together, our data suggest the existence of a non-canonical complex comprising INTS6L instead of INTS6, which only partially compensates for the loss of INTS6.