Theophylline (non-specific PDE inhibitor) and their interactions with nitric oxide modulators were evaluated in adjuvant-induced arthritic model of rats. Wistar rats (200–300 g), 8 animals per group were used in the study. The animals were injected with 0.1 mL of squalene and 0.2 mL of complete Freund's adjuvant on day (0) in sub-planter region of right hind paw controls received only saline. The treatment with theophylline and nitric oxide modulators were done from day 14 to day 28. Arthritis indexes, ankle diameter, paw volume, and body weight were determined to assess RA progression from day (0) to day 28. On day 28 animals were sacrificed and their blood collected for IL-10 and TNF-α cytokine levels and hind paw for pathological analysis. Synovial fluid from joint spaces of CFA inoculated rats was collected to estimate TNF-α level in synovial fluid. The data obtained was analyzed by two-way ANOVA followed by the Newman–Keuls post-hoc test. Theophylline (10 and 20 mg/kg) significantly decreased adjuvant induced increased arthritis-index, paw volume and ankle diameter (p < 0.05 in all parameters) compared to only adjuvant control group. It also reversed adjuvant induced slight decrease in body weight to normalcy. l-Arginine 100 mg/kg + theophylline 20 mg/kg suppressed TNF-α and elevates IL-10 level as well as reversed adjuvant-induced elevated arthritic parameters as compared to only adjuvant and prednisone group (p < 0.001). Synovial TNF-α level of adjuvant only group was several fold higher than its serum level. Treatment with theophylline 20 mg/kg significantly reduces synovial TNF-α level as compared to adjuvant only group. Theophylline 20 mg/kg + L-NAME 10 mg/kg significantly reversed these adjuvant-induced changes in immunological, histopathological and arthritis parameters (p < 0.05).