To assess the safety profile of iso‐osmolar contrast medium (CM) versus low osmolar CM in cancer patients with an estimated glomerular filtration rate (eGFR) >60 ml/min. In this multicenter, blind trial of patients seeking a chest‐abdomen‐pelvis contrast enhanced computed tomography (CT) with iodated CM, participants were centrally randomized to iodixanol or iopromide. Contrast induced nephropathy (CIN) at 24 and/or 72 hr were our primary outcomes. We further considered irreversible CIN, average eGFR percentage variation (%Δ), and adverse events (AEs). Overall, 607 patients were enrolled. Among them, 497 eligible patients were randomized to iodixanol (N: 247) or iopromide (N: 250). No differences emerged by descriptive characteristics. Seven and 3 CIN at 24 hr (p = 0.34) and 8 and 2 CIN at 72 hr (p = 0.11) occurred in the iopromide and iodixanol group, respectively. Within the subgroup of individual patients who developed CIN (N: 17), the event rate was higher in the iopromide arm (p = 0.045). No cases of permanent CIN or significant differences in terms of AEs or GFR %Δ were observed. Our results suggest a more favorable safety profile of iodixanol versus iopromide. Adequately sized trials with similar design are warranted to confirm our findings and clarify the underlying biological mechanisms. 1) This is a multicenter, blind trial of patients seeking a chest‐abdomen‐pelvis CT with iodated CM. 2) Aim of the study was to assess the safety profile of iso‐osmolar contrast medium (CM) versus low osmolar CM in cancer patients with an estimated glomerular filtration rate (eGFR) >60 ml/min. 3) No cases of permanent CIN or significant differences in terms of adverse events were observed.