Adrenal and extra-adrenal paragangliomas (PGLs) are a group of neuroendocrine tumors (NETs) with strong heterogeneity, which often express somatostatin receptor subtype 2 A (SSTR2A). However, the association between SSTR2A expression and genetic status of PGLs remains unclear. The purpose of the study was to identify whether various pathogenic variants (PVs) had an impact on SSTR2A expression in PGLs. This retrospective study included 184 patients with pathologically confirmed PGLs. The immunohistochemical expression of SSTR2A were studied in 184 tumors and PVs were tested in 159 tumor samples. Clinical and genetic data were compared in SSTR2A positive and negative PGLs. SSTR2A was positive in 63.6% (117/184) of all tumors. PGLs with negative SSTR2A were more likely to be extra-adrenal (37.0% vs 18.0%; P = 0.005) and exhibited a considerably greater proportion of PVs (75.4% vs. 49.0%; P = 0.001) than those with positive SSTR2A. Compared to those without PVs, a higher proportion of PGLs with PVs in cluster 1B (P = 0.004) and cluster 2 (P = 0.004) genes, especially VHL (P = 0.009), FGFR1 (P = 0.010) and HRAS (P = 0.007), were SSTR2A negative. SSTR2A was positive in all tumors (4/4) with SDHx PVs and in 87.5% (7/8) of metastatic PGLs. SSTR2A negativity was correlated with extra-adrenal tumor location and PVs in cluster 1B and cluster 2 genes such as VHL, FGFR1 and HRAS. Immunohistochemistry of SSTR2A should be taken into consideration in the personalized management of PGLs.