Cigarette smoke (CS) is convincingly carcinogenic in mice when exposure starts at birth. We investigated the induction and modulation of alterations in the kidney and urinary bladder of CS-exposed mice. A total of 484 strain H Swiss mice were either sham-exposed or exposed since birth to mainstream CS (MCS) for 4 months. Dietary agents, including myo-inositol, suberoylanilide hydroxamic acid, bexarotene, pioglitazone and a combination of bexarotene and pioglitazone, were administered after weaning. Comet analyses showed that, after 2 and 4 months, MCS causes DNA damage in exfoliated urothelial cells, which can be prevented by myo-inositol and the peroxisome proliferator-activated receptor-γ ligand pioglitazone. After 7 months, the 17.6% of MCS-exposed male mice exhibited lesions of the urinary tract versus the 6.1% of sham-exposed mice, which emphasizes the role of sex hormones in urinary tract carcinogenesis. Myo-inositol and the RXR-specific retinoid bexarotene did not affect these alterations. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (Vorinostat) increased the incidence of kidney epithelium hyperplasia. Pioglitazone significantly enhanced the incidence of kidney lesions as compared with mice exposed to MCS only, indicating possible adverse effects of this antidiabetic drug, which were lost upon combination with bexarotene according to a combined chemoprevention strategy. RXR is a heterodymeric partner for peroxisome proliferator-activated receptor-γ, thereby modulating the expression of multiple target genes. In conclusion, there is contrast between the ability of pioglitazone to inhibit DNA damage in exfoliated cells and the alterations induced in the urinary tract of MCS-exposed mice, suggesting the occurrence of non-genotoxic mechanisms for this drug.