This book constitutes the refereed proceedings of the 22nd International Conference on Product-Focused Software Process Improvement, PROFES 2021, held in Turin, Italy, in November 2021. Due to COVID-19 pandemic the conference was held as a hybrid event. The 20 revised papers, including 14 full papers, 3 short papers and 3 industry papers, presented were carefully reviewed and selected from 48 submissions. The papers cover a broad range of topics related to professional software development and process improvement driven by product and service quality needs. They are organized in the following topical sections: agile and migration, requirements, human factors, and software quality.