To study genetic diversity and drug resistance of HIV-1 CRF_BC among drug users in Guangdong Province, 67 circulating recombinant form 07_BC (CRF_07BC) and 32 circulating recombinant form 08_BC(CRF_08BC) HIV-1 pol genes were amplified and sequenced. In the protease gene region (PR), 31 CRF_08BC isolates were amplified and 10 high polymorphism positions were identified. The polymorphisms L19I, M36I, R41K, D60E, L63P, H69K, and I93L were complete substitutions, and were followed by T12S (94%), I15V (90%), and L89M (81%) separately. Five high polymorphisms were found in CRF_07BC isolates; there were E35D (88%), R41K (100%), D60E (96%), L63P (99%), and I93L (91%). Four of the identified polymorphism positions (R41K, D60E, L63P, and I93L) were the same in the PR region of both subtypes. In the reverse transcriptase (RT) region six high polymorphism positions, V35T, E36A, T39D/E/N, S48T, V60I, and V245Q, were identified in both subtypes. E53D (97%), I135V/T/R (81%), S162C (94%), Q207E (100%), and R211K (97%) were primarily in CRF_08BC subtypes and D121Y/H (97%) were primarily in CRF_07BC. The NRTI resistance mutation T69S was 94% (30/32) in CRF_08BC. To now, we have found no related reports concerning such high polymorphisms in the position. Polymorphisms V77M (PI) and K201Q (RT) were not found in the mutation profiles; therefore it may have been a new mutation in HIV-1. This study analyzed the difference between CRF_08BC and 07BC polymorphisms among drug users in Guangdong Province, which may help to guide recommendations for diagnostic assays, vaccine design, and antiretroviral regimen strategies in China.