In areas of southern Africa, aqueous extracts from the roots of Pelargonium sidoides are employed to cure various disorders. Nowadays, a modern formulation (EPs 7630), elaborated from the traditional herbal medicine, is successfully used for the treatment of respiratory tract diseases. We previously observed that root extracts of P. sidoides and their representative constituents exhibit moderate antibacterial and significant immunomodulatory capabilities. The present study was performed to further assess the efficacy and mode of action for these pharmacological activities. The results indicate that P. sidoides extracts may well possess antimycobacterial activity as claimed in traditional uses. Furthermore, significant antibacterial properties against multi-resistant Staphylococcus aureus strains as well as TNF-inducing potencies and prominent interferon-like activities in supernatants of sample-activated bone marrow-derived macrophages were observed using several functional assays. In addition, EPs 7630 stimulated the synthesis of IFN-beta in MG 63 cells as demonstrated by a specific enzyme immunoassay. For gallic acid, a characteristic constituent, evidence for the expression of iNOS and TNF-alpha transcripts in stimulated RAW 264.7 cells and, hence, activation at the transcriptional level was revealed by RT-PCR. The present results, when taken together with the recently reported pharmacological activities, provide for a rationale basis of the utilization of EPs 7630 in the treatment of respiratory tract infections.