We analyze decadal climate variability in the Mediterranean region using observational datasets over the period 1850–2009 and a regional climate model simulation for the period 1960–2000, focusing in particular on the winter (DJF) and summer (JJA) seasons. Our results show that decadal variability associated with the winter and summer manifestations of the North Atlantic Oscillation (NAO and SNAO respectively) and the Atlantic Multidecadal Oscillation (AMO) significantly contribute to decadal climate anomalies over the Mediterranean region during these seasons. Over 30% of decadal variance in DJF and JJA precipitation in parts of the Mediterranean region can be explained by NAO and SNAO variability respectively. During JJA, the AMO explains over 30% of regional surface air temperature anomalies and Mediterranean Sea surface temperature anomalies, with significant influence also in the transition seasons. In DJF, only Mediterranean SST still significantly correlates with the AMO while regional surface air temperature does not. Also, there is no significant NAO influence on decadal Mediterranean surface air temperature anomalies during this season. A simulation with the PROTHEUS regional ocean–atmosphere coupled model is utilized to investigate processes determining regional decadal changes during the 1960–2000 period, specifically the wetter and cooler 1971–1985 conditions versus the drier and warmer 1986–2000 conditions. The simulation successfully captures the essence of observed decadal changes. Model set-up suggests that AMO variability is transmitted to the Mediterranean/European region and the Mediterranean Sea via atmospheric processes. Regional feedbacks involving cloud cover and soil moisture changes also appear to contribute to observed changes. If confirmed, the linkage between Mediterranean temperatures and the AMO may imply a certain degree of regional decadal climate predictability. The AMO and other decadal influences outlined here should be considered along with those from long-term increases in greenhouse gas forcings when making regional climate out-looks for the Mediterranean 10–20 years out.