A shortage of COVID-19 vaccines and reports of side-effects led several countries to recommend a heterologous regimen for second vaccine doses. This study aimed to describe the reasons behind individuals’ choices of a homologous or a heterologous second vaccination. This cross-sectional study enrolled individuals under 60 who had received a first dose of Vaxzevria and could choose between a homologous or heterologous regimen for their second dose. Quantitative (socio-demographic, clinical characteristics) and qualitative data were collected and analysed through a generalized linear model and thematic analysis, respectively. Of the 1437 individuals included in the analysis, the majority (76.1%) chose a heterologous second dose of the COVID-19 vaccination. More females chose a heterologous vaccination regimen (p = 0.003). Younger individuals also tended to choose heterologous vaccination (p < 0.001). The main motivation in favour of heterologous vaccination was to follow the Italian Ministry of Health recommendations (n = 118; 53.9%). This study showed that most individuals, mainly younger people and females, chose a heterologous dose of COVID-19 vaccination after their first viral vector vaccine. Heterologous vaccinations could be an effective public health measure to control the pandemic as they are a safe and efficient alternative to homologous regimens.