Fourteen biochemical pollution biomarkers were analyzed in the clam Chamaelea gallina sampled at seven South-Spanish littoral sites at different times in 1999. They included enzymes that regenerate reduced nicotinamide adenine dinucleotide phosphate (NADPH) or maintain the cytosol-reduced (glucose-6-P- and isocitrate dehydrogenases, glutathione reductase), that decompose reactive oxygen species (catalase, superoxide dismutase, glutathione peroxidase), or detoxify glutathione-reactive electrophiles (soluble and microsomal glutathione transferases, glyoxalases II and I). The levels of reduced glutathione, malondialdehyde, and metallothionein and the glutathione redox status were also determined. Clams from Huelva sites with higher contaminant loads and metallothionein levels showed higher antioxidant and glutathione-related activities and a decreased glutathione level, lower malondialdehyde content, and a less oxidized glutathione status. This suggests that clams chronically exposed to contaminants released by Huelva and Guadalquivir Estuaries are better protected from oxidative stress than reference animals. Most biomarkers showed six-month cyclicity with up to threefold amplitudes, further supporting the inverse relationship between antioxidant defenses and oxidative damages. Thus the lower antioxidant defenses in June fit to maximum oxidative damages, whereas the high antioxidant defenses found in March and September through October agree with lower lipid damages and less oxidized glutathione status. The effect of environmental or endogenous factors on this cyclic response is discussed.