Abstract Background Perianal disease is rather common among Crohn’s disease (CD) patients and quality of life is often worsened by disease activity. This study aimed to assess the possible predictors of long-term quality of life after surgery for perineal CD. Methods Data of 50 consecutive patients operated on from 2014 to 2018 for perianal fistula or abscess were retrieved. Thirty-three of them had perianal CD while 17 of them had a sporadic perianal fistula and were enrolled as controls. Patients were interviewed with the Cleveland Global Quality of Life (CGQL) and SF-12 quality of life questionnaires. Disease activity was defined as the Harvey–Bradshaw Index (HBI) and Perianal Disease Activity Index (PDAI). Comparisons between CD and sporadic groups were carried out with non-parametric tests and log-rank test and multiple regression models were used to assess predictors of quality of life. Results The total CGQL score and that of all its items were significantly lower in CD patients compared with patients with the sporadic perineal disease (p < 0.05) while SF12 sub total did not differ in the two groups. At multivariate analysis, CD diagnosis and perineal disease activity index confirmed to be independent predictors of long-term overall quality of life measured with CGQL. SF-12 mental component (MCS) was predicted by PDAI (p = 0.005) and by HBI (p = 0.03) while SF-12 Physical Component (PCS) was independently predicted by PDAI (p = 0.008), oozing perineal fistulae (p = 0.01) and age at disease onset (p = 0.0003). Conclusion Long-term quality of life after surgery for perineal disease is worse in CD patients than in patients with sporadic perianal disease. Quality of life is predicted by local and systemic disease activity and age at disease onset.