A retrospective cohort study in China investigated the effect of tripterygium glycosides (TG) on serum albumin levels in patients with rheumatoid arthritis (RA) compared with methotrexate (MTX) or a combination of TG + MTX. The study included 146 patients on TG, 62 on MTX and 54 on TG + MTX, with serum albumin measured before and after treatment. At baseline, albumin levels were not significantly different between groups. After treatment, there was a significant decrease in mean serum albumin in the TG and TG + MTX groups, while the levels remained stable in the MTX group. The incidence of hypoalbuminemia increased from 3.4% to 26.0% (p < 0.001) after TG, from 0% to 18.5% (p < 0.001) after TG + MTX, but only from 1.6% to 4.8% (p = 0.001) with MTX. Multivariable logistic regression analysis showed that advanced age is a significant independent risk factor for hypoalbuminemia. Thus, treatment with TG alone or with MTX is associated with the development of hypoalbuminemia in RA patients, especially in the elderly.