Persons living with HIV should remain on antiretroviral therapy (ART) indefinitely; however, a switch in the drug regimen is often necessary. In order to investigate if reasons for switching ART changed over time, we retrospectively analyzed reasons for switching and characteristics of switches among patients at Santa Maria Annunziata Hospital (OSMA), Florence area, Tuscany, Italy, over two periods (November 2012-October 2013 and November 2014-October 2015). The reasons for switching were classified as: simplification; virologic failure; occurrence of co-morbidities; and drug tolerability/toxicity issues. In period 1 (2012-2013), 18% patients changed their regimen vs. 13.5% in period 2 (2014-2015) (p = 0.019). Among reasons for switching, switches for simplification significantly increased from 41% in period 1 to 53% in period 2 (p = 0.004), with an increasing use of single tablet regimens (p = 0.002); no other statistically significant differences were found in other reasons for switching in periods 1 and 2. Characteristics of patients and of switches were analyzed and described. According to our data, the main reason for switching is now simplification, reflecting the recent changes in recommendations aimed to enhance adherence and quality of life, and to minimize, at the same time, drug toxicity and side effects.