Background: Pegylated liposomal doxorubicin (PLD) was found to have improved toxicity profile, especially with regards to reduced cardiotoxicity. The objectives of this study were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of PLD in combination with cyclophosphamide and vincristine (PCV regimen) and describe the toxicities and response of this regimen. Methods: This was an open-label, single-center, single-arm phase I study utilizing a “3 + 3” design. The primary endpoint was the MTD of PLD, and the secondary endpoints included safety, objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Efficacy was evaluated using RECIST 1.1. PFS was defined as the time from treatment until disease progression or death. This study included cohort A and cohort B. Three dose levels were studied in cohort A, PLD 30 mg/m² (L1), 40 mg/m² (L2) or 50 mg/m² (L3) d1 + cyclophosphamide and mesna at 1 g/m²/d d1-2 + vincristine 1.5 mg/m²/d (≯2mg) d1 every 3 weeks. As the endpoint of the study could not be reached, we changed the dose of cyclophosphamide and mesna to 1.5 g/m²/d d1 in cohort B. Results: Eleven in cohort A and 34 in cohort B were enrolled, the median age was 6 years (range 1-15). Forty-three patients were eligible and evaluable for toxicity, and 35 (77.8%) patients were evaluable for response. Diagnoses were rhabdomyosarcoma (n = 29, 64.4%), Ewing's sarcoma (n = 4), and others. The median number of prior regimens was 2 (range 1-5). The most common adverse event (AE) was grade 3 or grade 4 neutropenia with a proportion of 90.9% and 65.5% in cohort A and cohort B, respectively. There was no significant difference in ORR (60% vs. 48%) and DCR (90% vs. 88%) between the two cohorts. The ORR (60% vs. 0, P = 0.019) and DCR (96.7% vs. 40%, P = 0.006) were significantly higher in Group 1 (rhabdomyosarcoma, Ewing's sarcoma, Wilm's tumor, fibrosarcoma, undifferentiated sarcoma) compared with Group 2 (neuroblastoma, osteosarcoma, embryonal sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor). The 12-month PFS of Group 1 was also better than Group 2 (79% vs. 60%, P = 0.041). Conclusions: The PCV regimen demonstrated an acceptable toxicity profile and promising clinical efficacy in pediatric patients with R/R rhabdomyosarcoma, Ewing's sarcoma, Wilm's tumor, fibrosarcoma, and undifferentiated sarcoma. Increasing the dose of cyclophosphamide did not improve the efficacy, but increased the toxicity. The RP2D for future studies is PLD 30 mg/m²/d for one day. Clinical trial information: NCT04213612.