Chemotherapy-induced diarrhea (CID) is a frequent chemotherapy adverse event in dogs. Yet, there is currently no consensus regarding its management. Smectite is a natural medical clay, widely used in the treatment of acute diarrhea in humans. The objectives of this study were to assess the efficacy of smectite in the management of CID in dogs, and to collect epidemiological data on CID. For each episode of diarrhea, dogs were randomized into 2 management groups: Smectite group, receiving smectite at 0.5 g/kg PO per day divided in 2-3 doses initiated at the start of CID; Control group, without initial medication. In both groups, rescue metronidazole was prescribed if CID progressed or was not improved within 48 hours. Sixty dogs were recruited and received 426 chemotherapy administrations between June 2017 and March 2019. The incidence rate of CID was 110/426 (25.8%, 95% CI: 21.7-30.2%), and significantly differed between the chemotherapeutic drugs administered (P < 0.001). Metronidazole was administered in 5/54 events (9.3%, 95% CI: 3.1-20.3%) in the Smectite group and in 40/56 events (71.4%, 95% CI: 57.5-82.3%) in the Control group (P < 0.001). The time to resolution of diarrhea was shorter (P < 0.001) in the Smectite group (median: 19.5 hours, interquartile range: 13.5-32 hours) compared to the Control group (median: 53 hours, interquartile range: 31.5-113.5 hours). The results of this study support the administration of smectite in the first-line management of CID in dogs. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.