Background For complicated skin and soft tissue infections (cSSTIs), inappropriate initial anti-infective treatment often leads to treatment failure. The microbial distribution in patients with extremities’ cSSTIs has been rarely reported. Moreover, whether gram-negative bacteria (GNB) should be covered in addition to gram-positive bacteria (GPB) has been always a difficult issue in the treatment of cSSTIs. Methods We retrospectively analyzed the microbial distribution and antibiotic susceptibility in 149 hospitalized patients with extremities’ SSTIs, and discussed the risk factors of extremities’ cSSTIs caused by GNB. Results 188 strains of pathogens were isolated, including 113 strains of GPB (64.9%), 61 strains of GNB (32.4%), and 5 strains of fungi (2.7%). Diabetes mellitus (OR=3.606, P =0.034), SSTI severity [moderate infection (OR=19.499, P <0.0001), severe infection (OR=20.114, P <0.0001)], and necrotizing infection (OR=6.064, P <0.0001) were risk factors of extremities’ cSSTIs caused by GNB. For patients with risk factors, ceftazidime, cefepime, piperacillin/tazobactam and carbapenems could be empirical anti-infective agents. Conclusions The results of our study showed that the most common bacteria identified in cSSTIs of the extremities were GPB. For patients with risk factors of extremities’ cSSTIs caused by GNB, the coverage of GNB should be taken into account.