Background and Purpose: Di-isononyl phthalate (DINP) is a high molecular weight phthalate widely used in the manufacture of polyvinyl chloride and other commercial products. This assessment aims to systematically evaluate the evidence base for DINP, including human and animal cancer studies and mechanistic data, to inform an overall conclusion regarding the carcinogenic potential of DINP in humans. Methods: Peer-reviewed DINP literature were identified from systematic searches conducted in PubMed and Embase, supplemented by hand searching. Publicly available good laboratory practice and/or guideline laboratory reports were identified through review of regulatory documents. Mechanistic data were organized according to the key characteristics of carcinogens (KCCs). All identified data underwent critical appraisal. Data were integrated using principles of WHO IPCS for human and animal cancer data alongside concepts for activity assessment of mechanistic data. Results: Four epidemiological studies that evaluated the association between DINP exposure (via DINP-specific metabolites) and cancer were identified. Three studies reported no statistically significant (SS) positive increases in breast cancer incidence or mortality risk associated with DINP exposure. A case-control study found a SS increase in prostate cancer risk associated with DINP exposure, but this finding was determined to represent an imprecise association because it was based on a very small sample size and lack of consideration of confounding or covariates except matching on age. Current evidence from human studies does not support an association between DINP and cancer in humans. Four reliable dietary rodent cancer bioassays (3 in rats, 1 in mice) were identified. Inconsistent SS increases in liver and kidney tumors, and mononuclear cell leukemia (MNCL) were reported. A SS increase in hepatocellular adenomas, carcinomas, and/or their combined incidence was observed in 3 of the 4 studies. Mode of action (MoA) analysis supports that DINP elicits liver tumors via the peroxisome proliferator-activated receptor alpha (PPARα) MoA, which is widely considered to lack human relevance. A small but SS increase in renal tubular carcinomas was observed in 1 of 2 studies in male F344 rats; it is postulated that DINP acts through the non-human relevant α2u-globulin nephropathy MoA. In the F344 but not SD rat bioassays, a dose-dependent and SS increase in MNCL was observed. MNCL is a common lesion in aging F344 rats and is not considered relevant in predicting human cancer. Collectively, these animal data provide strong evidence that DINP is unlikely to be a human carcinogen. A robust mechanistic dataset of 127 studies was identified, with endpoints mapping to 9 of 10 KCCs. Reliable data in exposed humans from 42 studies showed inconsistent findings for KCC2 (genotoxicity), KCC4 (epigenetic alterations), and KCC5 (oxidative stress). Reliable data from in vivo animal studies, in vitro assays (human and mammalian), and in silico models from 85 studies showed DINP was neither genotoxic (KCC2) nor immunosuppressive (KCC7). Inconsistent signals of activity were reported for KCC1 (electrophilic), KCC4 (epigenetic alterations), KCC5 (oxidative stress), and KCC8 (modulates receptor-mediated effects). Activity related to KCC10 (alters cell proliferation, cell death and nutrient supply) was evident in liver and kidney of in vivo rodent models, consistent with studies that demonstrated rodent-specific MoAs for kidney and liver tumors described above. Conclusions: Limited epidemiological data do not support an association between cancer outcomes in humans and exposure to DINP. While rodent bioassays have shown tumor formation following DINP exposure, the underlying MoAs are not considered relevant to humans. Mechanistic data support this interpretation, demonstrating a lack of genotoxicity and only inconsistent activity across the other 9 KCCs. Collectively, this systematic evaluation suggests that DINP is unlikely to be carcinogenic in humans.