There are studies about health-related quality of life (HRQoL) in patients with rheumatoid arthritis (RA), but few studies prospectively assessed HRQoL. The main purpose of this study was to analyze HRQoL in patients hospitalized due to RA exacerbation and observed over a planned 2-year follow-up in an outpatient setting. The study involved 42 women and 9 men, at mean age of 62.5 years (SD ± 12.6). The mean duration of the study was 22-23 months. The HRQoL analysis was performed using the SF-36 survey. At the beginning of the study, basic data on age, sex, selected biochemical (ESR, CRP, GFR, hemoglobin, plasma albumin, plasma protein), and clinical parameters (the duration of RA, VAS, DAS28, BMI, the presence of cardiovascular disease, diabetes, osteoporosis, osteoporotic fractures, osteoarthritis, neoplasm) were collected. Questionnaires were completed at the beginning and end of the study. Statistically significant reductions in HRQoL scores were observed in social functioning (SF; 0.42 vs 0.32, P < 0.05), whereas role-emotional health (RE; 0.48 vs 0.59, P < 0.05) and mental health (MH; 0.47 vs 0.54, P < 0.05) scores were increased. A decrease in the SF was positively correlated with the lack of osteoporosis at baseline (r = 0.35, P > 0.02). An increase in the MH was inversely correlated with BMI (r = -0.31, P < 0.05), and the level of hemoglobin (r = -0.32, P < 0.028) and positively correlated with the presence of osteoarthritis at baseline (r = 0.29, P < 0.05). In RA patients, dimensions of HRQoL as SF, RE, and MH could change within 2 years and these changes could be related to comorbidities. Although preliminary findings are promising, further studies are needed.