Ibrutinib has demonstrated a significant clinical impact in patients with de novo and relapsed/refractory chronic lymphocytic leukemia (CLL), even in cases with unfavorable cytogenetics and molecular markers. All CLL patients’ data treated at our Institute with ibrutinib have been retrospectively reviewed. Forty-six patients received ibrutinib either as frontline (10) or second or more advanced treatment (36). Five patients presented with TP53 mutations; 11 had the deletion of chromosome 17p; 17 displayed an unmutated immunoglobulin variable heavy chain status. The median number of cycles administered was 26. Among patients treated frontline, the best overall response rate (ORR) was 90.0%. In patients receiving ibrutinib as a second or later line ORR was 97.2%. Median progression-free survival was 28.8 and 21.1 months for patients treated frontline and as second/later line, respectively. Median overall survival was not reached for those treated frontline and resulted in 4.9 years for patients treated as second/later line. Grade 3–4 hematological toxicities were neutropenia, thrombocytopenia, and anemia. Grade 3–4 extrahematological toxicities included diarrhea, cutaneous rash, utero-vesical prolapse, vasculitis, and sepsis. Ibrutinib is effective and well tolerated in CLL. Responses obtained in a real-life setting are durable and the safety profile of the drug is favorable.