The 5-HT₃ antagonists, informally known as "setrons", are a class of drugs that act as receptor antagonists at the 5-HT₃ receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain. With the notable exceptions of alosetron and cilansetron, which are used in the treatment of irritable bowel syndrome, all 5-HT₃ antagonists are antiemetics, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by cancer chemotherapy and are considered the gold standard for this purpose.

The 5-HT₃ antagonists may be identified by the suffix -setron, and are classified under code A04AA of the WHO's Anatomical Therapeutic Chemical Classification System.

5-HT₃ antagonists are most effective in the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV), especially that caused by highly emetogenic drugs such as cisplatin; when used for this purpose, they may be given alone or, more frequently, with a glucocorticoid, usually dexamethasone. They are usually given intravenously, shortly before administration of the chemotherapeutic agent, although some authors have argued that oral administration may be preferred. The concomitant administration of a NK₁ receptor antagonist, such as aprepitant, significantly increases the efficacy of 5-HT₃ antagonists in preventing both acute and delayed CINV.

The 5-HT₃ antagonists are also indicated in the prevention and treatment of radiation-induced nausea and vomiting (RINV), when needed, and postoperative nausea and vomiting (PONV). Although they are more effective at controlling CINV—where they stop symptoms altogether in up to 70% of people, and reduce them in the remaining 30%—, they are just as effective as other agents for PONV.

Current evidence suggests that 5-HT₃ antagonists are ineffective in controlling motion sickness. A randomized, placebo-controlled trial of ondansetron to treat motion sickness in air ambulance personnel showed subjective improvement, but it was not statistically significant.

Alosetron and cilansetron—the latter was developed by Solvay but never approved by the FDA —are not antiemetics; instead, they are indicated in the treatment of a subset of irritable bowel syndrome where diarrhea is the dominant symptom. Alosetron was withdrawn from the U.S. market in 2000 due to unacceptably frequent severe side effects, including ischemic colitis, and is only available through a restrictive program to patients who meet certain requirements.

Certain prokinetic drugs such as cisapride, renzapride and metoclopramide, although not 5-HT₃ antagonists proper, possess some weak antagonist effect at the 5-HT₃ receptor. Galanolactone, a diterpenoid found in ginger, is a 5-HT₃ antagonist and is believed to at least partially mediate the anti-emetic activity of this plant. Mirtazapine is a tetracyclic antidepressant with 5-HT₂ and 5-HT₃ antagonist effects that also possesses strong anti-emetic properties, however it is also very sedating. Studies show that Mirtazapine is as equally effective in treating chemotherapy-related nausea and vomiting as standard treatments; it is also cheaper and has fewer side effects than typical anti-emetics, and its antidepressant qualities may be an added benefit for cancer populations. Mirtazapine has also been used in the treatment of the motility disorder gastroparesis due to its anti-emetic effects. Olanzapine, an atypical antipsychotic with anti-emetic properties similar to those of mirtazapine, also shows promise in treating chemotherapy-induced nausea and vomiting.

There are few side effects related to the use of 5-HT₃ antagonists; the most common are constipation or diarrhea, headache, and dizziness. Unlike antihistamines with antiemetic properties such as cyclizine, 5-HT₃ antagonists do not produce sedation, nor do they cause extrapyramidal effects, as phenothiazines (such as prochlorperazine) sometimes do.