Background <p>During the last decades, there has been a great interest on the link between macroeconomic conditions and health. More precisely, many studies had studied as health outcome cardiovascular disease mortality, focusing in different countries, determinants, and using numerous econometric techniques. Due to its importance, in this paper, we analyse cardiovascular disease mortality across the 17 Spanish regions over the period 2002–2019.</p> Methods <p>In doing so, we estimated several panel data models considering differences by sub-periods of time while also considering gender differences. That is, we transmit a difference on previous evidence by considering a longer period of time and different explanatory factors, so we provide new highlights for Spain.</p> Results <p>Our empirical results show that: (i) both socioeconomic and environmental factors have a significant importance; (ii) political factors appear not to be significant; and (iii) there exists a Mediterranean (macro-region) cardiovascular disease mortality pattern.</p> Conclusions <p>These results may have usefulness for cardiovascular disease mortality prevention in Spain.</p>