Background <p>Limited data exist on the use of novel iron therapies in children with chronic kidney disease (CKD). We conducted a cross-over study to compare iron polymaltose complex (IPC) and liposomal iron in pediatric patients with CKD and iron deficiency anemia (IDA).</p> Methods <p>Cross-over study of 33 children with CKD and IDA was conducted. They were randomized into 2 groups (group A: 17 patients, group B: 16 patients) to receive either liposomal iron or IPC for 3&#xa0;months. After an 8-week washout period, they were switched to the other therapy. Red cell and iron indices, as well as bone minerals and 25(OH)D₃, were measured at baseline and after each 3-month period. A follow-up visit was conducted at 4&#xa0;weeks during the treatment period to report any possible adverse events.</p> Results <p>Hb levels increased by at least 1&#xa0;g/dL in 48% following liposomal iron therapy and 51.5% following IPC therapy. There was no statistically significant difference in ΔHb, ΔFe, ΔsTR (transferrin receptor), or ΔTSAT (transferrin saturation) levels between the groups (<i>p</i> &gt; 0.05). By mixed model analysis, IPC showed a higher Hb and TSAT and lower TRresponse compared with liposomal iron. IPC, but not liposomal iron, led to a significant reduction in serum phosphorus in both groups. Thirty-six percent of IPC recipients experienced adverse effects, compared to 3% of liposomal iron recipients.</p> Conclusions <p>Both IPC and liposomal iron effectively improved iron status in children with CKD and IDA. However, IPC indicated a superior response, whereas liposomal iron was associated with a more favorable tolerability profile.</p> Graphical abstract <p></p>