OBJECTIVES: Explore the relationship between obesity and health-related quality of life (HRQoL) in patients with moderate to severe psoriasis (PsO) or rheumatoid arthritis (RA). METHODS: A retrospective analysis on secondary clinical trial assessed 1,205 PsO and 1,988 RA patients using several approaches: (1) two univariate regression analyses [obesity predicting HRQoL; disease severity predicting HRQoL] and (2) a stepwise multivariate multiple regression analysis (MVA) to assess obesity as an independent predictor of HRQoL. Disease severity was measured using the PASI for PsO and DAS for RA. SF-36 was used for HRQoL assessment in both diseases. RESULTS: Obesity and disease severity were found to be significant predictors of HRQoL. The stepwise MVA, using BMI, age, sex, disease duration and disease severity as predictors, revealed an overall significant effect in the PsO sample [components: L=0.84, F (10, 2396) = 21.10, p <0.0001; SF-36 domains: L=0.73, F (40, 5198.6) = 9.54, p <0.0001]. BMI added to the prediction of HRQoL over PASI for several SF-36 components and domains: PCS, MCS, PF, RE, SF, VT and MH. The results of the RA sample were similar: the overall MVA was significant [components: L=0.74, F (10, 3962) = 64.05, p <0.0001; SF-36 domains: L=0.61, F (40, 8611.9) = 25.81]. Again, BMI added to the prediction of HRQoL over disease severity for MCS, PF and VT. Effect sizes in both samples were weak. CONCLUSION: Obesity was an independent predictor of HRQoL when using other covariates. This data indicates that reducing BMI and disease severity contribute significantly to the HRQoL of moderate to severe PsO and RA patients.