Purpose: The Quality of Life in Short Stature Youth (QoLISSY) questionnaire is a disease-specific instrument developed to assess health-related quality of life (HrQoL) in children with short stature. While the original instrument was simultaneously developed in five European countries, this study describes the results of the Italian QoLISSY translation, cultural adaptation, and validation. Methods: Focus group discussions and a cognitive debriefing process with children (N = 12) diagnosed with growth hormone deficiency or idiopathic short stature and one parent each, as well as parents of younger children (N = 20) were conducted to examine the linguistic and content validity of the Italian version. Psychometric testing was performed using data from the subsequent field- and re-test (N = 32). Results: The results of the qualitative testing of the Italian sample revealed comparability of content to data of the original five European countries. The following field- and re-test results were psychometrically satisfactory including good item and scale operating characteristics, sufficient evidence of reliability, and acceptable evidence of construct validity. Conclusion: In conclusion, the Italian QoLISSY HrQoL-dimensions are comparable to other European countries. The psychometric quality of the Italian QoLISSY version is satisfactory and the instrument is ready for use in Italian patients and their parents.