Although elderly patients have been reported to be less prone to chemotherapy-induced nausea and vomiting (CINV), its management is complicated by a high frequency of comorbidities and polypharmacy and an increased risk of dehydration and impaired cognition. The comparative efficacy and tolerability of palonosetron and ondansetron/dolasetron were assessed in a retrospective post hoc analysis using pooled data from 171 elderly patients (age > or = 65 years) with cancer enrolled in two randomized, double-blind, phase III clinical studies comparing single IV doses of these antiemetic agents given prior to receipt of moderately emetogenic chemotherapy. The complete response rate during the postchemotherapy period was significantly higher in the palonosetron group than in the ondansetron/dolasetron group in the 5 days following chemotherapy. The proportion of patients who were nausea-free on the problematic days 2 and 3 post chemotherapy and the time to treatment failure also significantly favored palonosetron. In this population that included patients with pre-existing comorbidities, palonosetron was well tolerated, with similar or fewer adverse events than the comparators. Comparisons in electrocardiogram parameters revealed that the mean postdose change from baseline in QTc interval was 3 ms for palonosetron 0.25 mg and 5 ms for ondansetron/dolasetron. In this retrospective analysis, palonosetron provided superior efficacy to ondansetron/dolasetron for the treatment of CINV in elderly patients receiving moderately emetogenic chemotherapy. Based on its safety profile, antiemetic control, and convenient dosing, palonosetron can be recommended for use in elderly patients with cancer receiving emetogenic chemotherapy.