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To characterize the adenoviral properties required to enhance intracellular transgene expression for gene therapy.Primary human fibroblasts and macrophages were infected with standard replication-defective adenoviruses, adenoviral vectors containing modified fiber coat proteins expressing Arg-Gly-Asp (RGD) or heparin sulfate binding moieties, or a tetracycline-regulatable transgene transcription system. Each of these vectors expressed the beta-galactosidase gene (beta-Gal), which was quantified by flow cytometry. Ankle joints from rats with adjuvant induced arthritis were transduced intraarticularly with each of the vectors and B-Gal expression was quantified by flow cytometry.Primary human fibroblasts and macrophages displayed marked increases in transgene expression from both modified fiber protein vectors and from the tetracycline-regulatable vector, compared to an unmodified vector expressing the transgene from the cytomegalovirus promoter/enhancer. In the rat model, the modified fiber protein vectors and the tetracycline-regulatable vector system also displayed increased transgene expression in inflamed rat joints.Adenovirus attachment and uptake by cells and promoter strength limit transgene expression from conventional adenoviral vectors in models of rheumatoid arthritis.