Objective: To evaluate the immunomodulatory activities of some of the common lichen compounds by using chemiluminescence based cellular assays.Methods: Number of secondary lichen metabolites, representing a breadth of lichen substances, were investigated for their effects on the respiratory burst of human whole blood phagocytes, isolated human polymorphonuclear leukocytes (PMNs) and murine macrophages using luminol or lucigenin-based chemiluminescence probes. Results: This study identify a clear suppressive effect of some lichen metabolites on phagocytosis response upon activation with serum opsonized zymosan by several lichen substances. Amongst the compounds tested, orsellinic acid, methyl orsellinate, methyl haematomate, lecanoric acid and lobaric acid, showed a potent immunomodulatory activity as compared to the standards. The lobaric acid suppressed both the myloperoxidase dependent and myloperoxidase independent, Reactive Oxygen Species (ROS) production in the oxidative burst of polymorphonuclear neutrophils (PMN) at the lowest concentration tested (3.1 µg/ml). Whereas, lecanoric acid, suppressed only the myloperoxidase dependent ROS production with IC50< 3.1µg/ml when compared to the standard sodium diethyldithiocarbamate trihydrate (SDT) (IC50 = 1.3 ± 0.2 µg/ml). Orsellinic acid, methyl orsellinate and methyl haematomate showed a selective myloperoxidase independent pathway with IC50 values; < 3.1µg/ml; 6.1 ± 1.0 µg/ml; 3.3 ± 0.1 µg/ml, respectively, being lower as compared to standard SDT (IC50 = 8.2 ± 1.9 µg/ml). Conclusion: Based on the results obtained it is appropriate to conclude that lichen are not only a good source of antioxidants, but also potent immunomodulators, and thus deserve to be investigated further.Â