Resistant hypertension (RH) is associated with organ damage and cardiovascular risk. Evidence suggests the involvement of matrix metalloproteinase 2 (MMP‐2) and tissue inhibitor of metalloproteinase 2 (TIMP‐2) in hypertension and in cardiovascular remodeling. The aim of this study was to assess the levels of MMP‐2 and TIMP‐2 in RH and its relation with organ damage, including arterial stiffness and cardiac hypertrophy. MMP‐2 and TIMP‐2 levels were compared among 19 patients with normotension (NT), 116 with nonresistant hypertension (HTN) and 116 patients with resistant HTN (RH). MMP‐2 levels showed no differences among NT, HTN, and RH groups, while TIMP‐2 levels were higher in RH compared with HTN and NT groups (90.0 [76.1–107.3] vs 70.1 [57.7–88.3] vs 54.7 [40.9–58.1] ng/mL, P<.01), respectively. MMP‐2/TIMP‐2 ratio was reduced in the RH group compared with the HTN and NT groups (2.7 [1.9–3.4] vs 3.3 [2.6–4.2] vs 4.9 [4.5–5.3], P<.01), respectively. No associations were found between MMP‐2 levels, TIMP‐2, and MMP‐2/TIMP‐2 ratio with cardiac hypertrophy and arterial stiffness in the RH and HTN groups. Finally, in a regression analysis, reduced MMP‐2/TIMP‐2 ratio and increased TIMP‐2 levels were independently associated with RH. The present findings provide evidence that TIMP‐2 is associated with RH and might be a possible biomarker for screening RH patients.