The objectives of the present study were to evaluate heterosis for grain yield and yield components in durum wheat, and to assess the prediction potential of amplified fragment length polymorphism (AFLP) based and agronomic trait based genetic distances (GD and MD, respectively) to F1 performance, mid parent heterosis (MPH), and specific combining ability effects (SCA) under well-watered and moisture stress conditions. Six parental genotypes with different responses to moisture stress and their 15 F1 crosses were evaluated for their responses to moisture stress conditions in a glasshouse. Some cross combinations showed significant MPH for grain yield and yield components. The expression of heterosis for grain yield was greater under moisture stress conditions than under well-watered conditions. Cluster analysis of the parental lines based on agronomic performance under stress conditions was similar to cluster analysis result based on AFLP marker profiles. F1 performance was strongly correlated to both SCA effects and MPH under both stress and well water conditions. The correlation between SCA and MPH was very high under both treatment conditions for all traits. Correlation between GD and MD was significant only under stress conditions. Positive correlation was found only for the association between GD v. F1 performance and GD v. SCA effects for harvest index (HI) under well-watered conditions. None of the correlations between MD and SCA effects were significant. The absence of association between GD and heterosis for yield and most agronomic traits implied that heterozygosity per se diversity is not a good predictor of heterosis or F1 performance under both well-watered and stressed conditions.