Background: Perianal infections (PIs) are a serious threat in patients with acute myeloid leukemia (AML). While CPX-351 is designed to reduce gastrointestinal toxicity, its impact on the incidence of PIs is unknown. This study aims to evaluate the incidence and characteristics of PIs in a cohort of CPX-351-treated AML patients. Methods: We enrolled 22 adult patients diagnosed with secondary AML receiving CPX-351 between May 2020 and July 2025 at Policlinico Tor Vergata Hospital. Statistical analysis used descriptive statistics and univariate analysis. Results: The incidence of PIs in the cohort was 31.8%. Microbiological cultures from the lesions commonly yielded Klebsiella pneumoniae and Enterococcus species. The development of a PI was associated with a significantly longer hospital stay (mean, 49.6 vs. 37.7 days; p = 0.034). A trend was noted between the presence of PIs and mucositis (p = 0.05) and positive rectal swabs (p = 0.09), with two patients (28.5%) having a positive pre-infection swab for Klebsiella pneumoniae. Surgical intervention was guided by patient pain levels and hematological criteria. Surgical patients had significantly higher pain levels and a platelet count greater than 20 x 10^9/L. All patients were alive at 30 days, with low rates of septic shock (14.2%, n=1) and no infection-related mortality or recurrence. Conclusions: Despite CPX-351′s known reduced gastrointestinal toxicity, our study showed a significantly higher incidence of PIs compared to literature data. While the outcomes were favorable, PIs led to prolonged hospitalization. Routine rectal swab surveillance could be a valuable tool for risk stratification and preemptive strategies.