OBJECTIVE Tetracyclines have been recognized as useful agents for therapy of inflammatory arthritides. However, prolonged use of tetracyclines is limited by their detrimental antimicrobial properties. Recently, a group of chemically modified tetracyclines (CMT) devoid of antimicrobial properties has been synthesized. Some CMT were found to inhibit various matrix metalloproteinases (MMP). We reported previously that antimicrobial tetracyclines inhibit the activity of proinflammatory secretory group II phospholipase A2 (sPLA2). The objective of this study was to detect whether non-antimicrobial CMT also inhibit sPLA2 and other phospholipases A2. METHODS Ten synthetic CMT were tested for inhibition of sPLA2 human and porcine PLA2, and Naja naja PLA2. PLA2 activity was assessed by radiolabeled Escherichia coli assay using standard and high calcium concentrations. RESULTS Six of 10 CMT inhibited sPLA2 activity at concentrations close to or lower than 50 microg/ml. All 6 CMT had identical C1-3 and C10-12a positions in the 4-ringed nucleus of the tetracycline molecule. Calcium concentrations up to 20 mM did not eliminate the inhibitory activity of CMT. Inhibition of other PLA2 was induced by some CMT, all but one (CMT-9) belonging to the group of strong inhibitors of sPLA2. Thus, inhibition of PLA2 different from sPLA2 does not necessarily require identical C1-3/C10-12a residues. CONCLUSIONS Since CMT, which inhibit proinflammatory sPLA2, are also inhibitors of some MMP, they may be useful for therapy of inflammatory diseases in which both MMP and sPLA2 are overexpressed.