Electronic commerce (e-commerce) is widening the concept of business from a simple transactional approach to a broader and more complex concept of inter-firm co-operation. Amidst market globalization, growing interpenetration of national economies and the increased interdependence of national economies, e-commerce adoption remains a vital yet complex and elusive phenomenon, with very little known about its determinants. This study identifies the major determining factors in Ghanaian small and medium sized enterprises’ (SMEs) e-commerce adoption, offers practical implications, and indicates the actions required. This research integrates technological, organizational, and environmental determinisms with social constructivism to build a practical framework for understanding e-commerce adoption among SMEs in Ghana. Structural equation modeling was employed for data analysis. The results indicate that government support has the greatest direct impact on intentions to use e-commerce. Managerial support and the influence of enabling and regulatory conditions also play a vital role in stimulating SME e-commerce adoption in Ghana. The results also show that Ghanaian SMEs tend to imitate successful first-movers to avoid the risks that attend e-commerce technology.