We investigate the clinical association of tumor necrosis factor receptor 2 (TNFR2) M196R polymorphism with rheumatoid arthritis (RA) and knee osteoarthritis (OA). Acute phase reactants, lipid profile, sTNFR2 levels, disease activity-disability indexes, and TNFR2 M196R polymorphism were analyzed in 50 RA, 50 knee OA patients, and 120 healthy subjects (HS). The M/M genotype frequency was 0.74 (RA), 0.80 (OA), and 0.64 (HS). The M/R genotype frequency was RA (0.26), OA (0.20), and HS (0.29). The R/R genotype was observed only in HS (0.07). The M allele was associated with OA (P = 0.0137, OR = 2.43). Total cholesterol, triglyceride levels, apolipoprotein A-I and B showed significant differences (P < 0.05). The highest sTNFR2 levels were observed in RA and OA (P = 0.001), however M/M and M/R carriers do not correlate with sTNFR2 production. Our findings suggest an association of the M allele with knee OA. In addition, high sTNFR2 levels in RA and OA were found.