Amazonian forests are being rapidly cleared, and the remaining forest fragments appear unusually vulnerable to fire. This occurs because forest remnants have dry, fire-prone edges, are juxtaposed with frequently burned pastures, and are often degraded by selective logging, which increases forest desiccation and fuel loading. Here we demonstrate that in eastern Amazonia, fires are operating as a large-scale edge effect in the sense that most fires originate outside fragments and penetrate considerable distances into forest interiors. Multi-temporal analyses of satellite imagery from two frontier areas reveal that fire frequency over 12-14-y periods was substantially elevated within at least 2400 m of forest margins. Application of these data with a mathematical core-area model suggests that even large forest remnants (up to several hundred thousand ha in area) could be vulnerable to edge-related fires. The synergistic interactions of forest fragmentation, logging and human-ignited fires pose critical threats to Amazonian forests, particularly in more seasonal areas of the basin.