Needle-induced trauma is one of the major contributing factors for poor compliance in patients with thalassaemia major on iron chelation therapy. A new generation of needles is currently available on the market, but their theoretical advantages have not been tested clinically. We performed a study to compare the pros and cons of the representative prototypes from each of the new (Thalaset needle) and old (butterfly scalp vein needle) generations of needles. Patients with thalassemia major who had been receiving subcutaneous iron chelation therapy for at least 2 years were recruited. Patients using butterfly needles were instructed to switch to the newer form of needle (Thalaset) for 2.5 months and then to change back to butterfly needles for another 2.5 months. Comparison was done by the intrapersonal cross-over model using three identical sets of questionnaires collected at the beginning of the study and after the use of Thalaset and butterfly needles, respectively. Fifty-four (22 females; 32 males) patients were included in the statistical analysis. The median age was 24.1 years (range = 7.6-47.2 years). Local reactions such as pain, itchiness, tenderness, and swelling were significantly different among the three evaluation periods and were all in favor of the Thalaset needle (all with P < 0.001), even after adjusting for the intention-to-treat calculation. The Thalaset needle is significantly better than the butterfly needle in reducing needle-related trauma. It induced fewer local skin reactions such as pain, itchiness, tenderness, and swelling. However, recommendations for its routine clinical use require further cost-effectiveness analysis.