Mallory-Denk bodies (MDBs) are hepatocyte inclusions found in several liver diseases and consist primarily of keratins 8 and 18 (K8/K18) and ubiquitin that are cross-linked by transglutaminase-2. We hypothesized that genetic variables contribute to the extent of MDB formation, because not all patients with an MDB-associated liver disease develop inclusions. We tested this hypothesis using five strains of mice (FVB/N, C3H/He, Balb/cAnN, C57BL/6, 129X1/Sv) fed for three months (eight mice per strain) the established MDB-inducing agent 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). MDB formation was compared using hematoxylin-and-eosin staining, or immunofluorescence staining with antibodies to K8/K18/ubiquitin, or biochemically by blotting with antibodies to transglutaminase-2/p62 proteins and to K8/ K18/ubiquitin to detect keratin cross-linking. DDC feeding induced MDBs in all mouse strains, but there were dramatic strain differences that quantitatively varied 2.5-fold (P < 0.05). MDB formation correlated with hepatocyte ballooning, and most ballooned hepatocytes had MDBs. Immunofluorescence assessment was far more sensitive than hematoxylin-and-eosin staining in detecting small MDBs, which out-numbered (by ∼30-fold to 90-fold) but did not parallel their large counterparts. MDB scores partially reflected the biochemical presence of cross-linked keratin-ubiquitin species but not the changes in liver size or injury in response to DDC. The extent of steatosis correlated with the total (large+small) number of MDBs, and there was a limited correlation between large MDBs and acidophil bodies. Conclusion: Mouse MDB formation has important genetic contributions that do not correlate with the extent of DDC-induced liver injury. If extrapolated to humans, the genetic contributions help explain why some patients develop MDBs whereas others are less likely to do so. Detection and classification of MDBs using MDB-marker-selective staining may offer unique links to specific histological features of DDC-induced liver injury.