Introduction and Aims: Being best-studied superficial bladder cancer (SBC) chemopreventives, retinoids’ negative studies and toxicity were stumbling. With proper understanding of retinoid metabolism, we aimed at investigating combined ketoconazole (a strong inhibitor of retinoic acid-catabolizing cytochrome P450s)-all-trans retinoic acid (Keto-atRA) SBC treatment. VEGF and TGF-α levels are end-point pathogenetic biomarkers involved in early SBC. Material and Methods: Seven days after TURT visible tumor(s), combined atRA 1 mg/kg for 5 days/week + Keto 200 mg twice daily for 5 days/week for 3 months were given to 16 patients with SBC stages Ta and T1 with various grades. 3 months follow up/20 months used white light cystoscopy and urinary cytology. Recurrence rate and survival time were compared to a retrospective group of 25 patients of comparable age, stage and grade with TURT as sole treatment for SBC. VEGF and TGF-α were measured in urine and serum of 12 normal subjects and treated patients. Samples were collected just before TURT, 1 week after TURT, at the end of 1 month and at the end of 3 months of treatment. Results: Keto-atRA treatment significantly improved survival time and decreased recurrence rate compared to control disease group, with tolerable and reversible side-effects. Treatment normalized induced levels of VEGF and TGF-α with a positive correlation between these cytokines. Conclusions: The combination and schedule used for Keto-atRA therapy effectively reduced recurrence rate and increased survival time of SBC patients probably through reduction of VEGF and TGF-α as major mitogenic/angiogenic factors; possibly by eliminating malignant cells that produce them.