Immunotherapy with intravesical instillation of bacillus Calmette-Guérin (BCG) is an effective treatment for superficial bladder carcinoma. In the present study the BCG-induced immunological reaction in the guinea pig (PPD skin test, bladder wall infiltrates and number of cells in the iliac lymph nodes) was investigated after intravesical pretreatment with pentosan polysulphate (PPS), which modulated BCG attachment to the bladder wall. Pentosan polysulfate is a molecule comparable to the naturally occurring glycosaminoglycans (GAGs) of the bladder mucosa. The data obtained after six weekly instillations of BCG-RIVM (5 x 10(6) - 5 x 10(7) cfu) with or without preinstillation with PPS (10 mg. in 1 ml. for 0.5 hour) suggested an elevation of the immunological reaction to intravesical BCG. A strong binding capacity of PPS to the mammalian bladder wall was observed. In addition, and in contrast to bacteria commonly causing cystitis, a significant binding of PPS to mycobacteria was found: 3.5, 3.6 and 3.1 micrograms./ml. dry weight of BCG Connaught, RIVM and Pasteur, compared with 0.2, 0.3, 0.7 and 0.0 microgram./mg. dry weight of Escherichia coli, Streptococcus faecalis, Klebsiella pneumoniae and Proteus. The results suggest that PPS enhances the attachment of BCG to the bladder wall, resulting in an increased BCG-induced immunological reaction in the guinea pig. It may be speculated that pretreatment with PPS may increase the efficacy of BCG therapy in man, especially in those patients not exhibiting an immunological reaction.