Background: Heterosexual intercourse accounted for 93% of reported HIV cases in Guangxi, and Guangxi had 10% of China's total number of reported HIV cases. Older men are particularly vulnerable to STIs, for example, 46% of Guangxi's HIV cases were men over 50 years of age. As this is an under-studied population in China, effective prevention and control policies have yet to be developed. Thus, the aim of this study was to use a large-scale cross-sectional survey to understand the demographic and behavior factors associated with HIV and syphilis infections among older male clients of female sex workers (FSWs) in a high epidemic area of rural Guangxi, China. Methods: A large-scale cross-sectional survey was conducted in 2012 among older male clients of FSWs in low-cost commercial sex venues. Questionnaire interviews were administered to collect sociodemographic and sexual behavior information. Blood samples were collected for HIV and syphilis infection tests. Results: Of the 3485 participants, 2509 (72.0%) clients had a steady sex partner and 976 (28.0%) clients had no steady sex partner. The overall prevalence of HIV and syphilis infection were 3.0% and 3.2%, respectively. Compared to those with a steady sex partner, clients with no steady partner had higher odds of HIV infection (AOR: 1.90, 95% CI: 1.27-2.86), syphilis infection (AOR: 1.53, 95% CI: 1.02-2.30), and having factors associated with HIV or syphilis infection, including non-commercial casual sex encounters in last month (AOR: 3.29, 95% CI: 2.42-4.46), >10 years of commercial sex history (AOR: 1.31, 95% CI: 1.12-1.53), >2 incidents of commercial sex in last month (AOR: 1.53, 95% CI: 1.19-1.96), and aphrodisiac use in last month (AOR: 1.40, 95% CI: 1.16-1.70). Clients with no steady partner had lower odds of having heterosexual intercourse (AOR: 0.66, 95% CI: 0.56-0.79), awareness and knowledge of HIV/AIDS (AOR: 0.75, 95% CI: 0.64-0.88), and having had HIV tests (AOR: 0.65, 95% CI: 0.44-0.98). Conclusion: Older male clients of low-cost commercial sex venues in rural southwestern China are at high risk for HIV and syphilis infection, especially those with no steady sex partner. Improved interventions are urgently needed for this neglected risk population.