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Rheumatoid arthritis ( RA) is one of autoimmune disease because of oxidative stress that would increase the number of CD4+ cells. It will cause inflammatory and damage in synovial membrane and joints. Conventional therapy which used to overcome inflammatory by administering non-steroid anti-inflammation drugs (NSAID) are able to make bleeding and damage gastrointestinal tract and liver. Red betel (Piper crocatum) content flavonoid which has oxidant activity. This research was conducted to determine the effect of red betel leaf extract on the number of CD4 + cells and to find dose are able to reduce number CD4 + cells in RA mice. The animal used were eight weeks of male balb C strain mice were eight weeks with ranged of weight from 28-30 grams. Mice will divide into six groups (normal, RA without therapy, aspirin therapy, therapy by red betel leaf extract dose 100 mg/g, 200 mg/g and 400 mg/g). Each treatment was delivered by gavage with 0.5 ml for 21 days. At the end of treatment, The mice were sectioned and lymphocytes were isolated to count the number of CD4 + cells using flowcytometry. The results showed leaf extract of red betel has an effect to decrease the number of CD4 + cells on RA mice, whereas leaf extract of red betel optimal dose is 200 mg/g and has a tendency to decrease the number of CD4 + cells.