The aim of this multicenter, quantitative, observational study was to analyze compliance and re-training needs of patients on peritoneal dialysis (PD) through the assessment of patient knowledge (with a Patient Questionnaire; phase 1) and patient behavior (home visit with a Score Card; phase 2). A total of 353 patients from 11 Italian centers participated in the first phase and 191 patients from nine centers in the second phase. Overall, 66% of questions on the Patient Questionnaire were answered correctly. Correct answers were more frequent in females than males, in patients under 55 years of age, and in those with higher education. The lowest rate of correct answers involved questions related to diet and physical activity (67% and 51%, respectively). Data collected during the home visit showed that 25% of patients were partially compliant with their drug therapy. Twenty-three percent of patients were non-compliant with the exchange protocol procedures, with a significant association between compliance and the incidence of peritonitis, and 11% were non-compliant with the exit-site protocol procedures without a statistically significant correlation to peritonitis. By combining the two evaluations, we found that approximately one-third (29%) of patients needed reinforcement of knowledge and ability to correctly perform PD as related to infection control and 27% for the correct use of drugs. Looking at the combined evaluation of infection control and drug use, results showed that 47% of patients needed re-training. This need for re-training was greater for younger patients (less than 55 years old), patients with lower education degree and patients in the early or late phase of PD therapy (less than 18 months or more than 36 months). Gender and degree of autonomy had no effect on the need for re-training.