External application of static magnetic fields (SMF), used specifically for the treatment of inflammatory conditions such as soft tissue injuries, has recently become popular as a complementary and/or alternative therapy with minimal investigation into efficacy or mechanism. Localized inflammation was induced via injection of inflammatory agents lambda-carrageenan (CA) or histamine into rat hindpaws, alone or in conjunction with pharmacological agents, resulting in a spatially and temporally defined inflammatory reaction. Application of a 10- or 70-mT, but not a 400-mT, SMF for 15 or 30 min immediately following histamine-induced edema resulted in a significant, 20-50% reduction in edema formation. In addition, a 2-h, 70-mT field application to CA-induced edema also resulted in significant (33-37%) edema reduction. Field application before injection or at the time of maximal edema did not influence edema formation or resolution, respectively. Together, these results suggest the existence of a therapeutic threshold of SMF strength (below 400 mT) and a temporal dependence of efficacy. Administration of pharmacological agents directed at nitric oxide signaling and L-type Ca(2+) channel dynamics in conjunction with SMF treatment and histamine-induced edema revealed that the potential mechanism of SMF action may be via modulation of vascular tone through effects on L-type Ca(2+) channels in vascular smooth muscle cells.