Southern Peru and northern Chile (17–30°S, 67–74°W) make up a seismically active region due to the convergence of the Nazca Plate and the South American Plate. The region has experienced a number of destructive earthquakes and tsunamis over the past few centuries, which have caused loss of human life and significant damage to infrastructure, highlighting the importance of seismic hazard assessment in the region. In fact, a reliable seismic hazard assessment is critical for developing policies for seismic hazard mitigation and risk reduction. In this study, we performed a probabilistic seismic hazard assessment (PSHA) of the study area based on an earthquake catalog that was very carefully analyzed. In earlier studies, we demonstrated that inappropriate treatment of the earthquake catalog can result in a serious bias in evaluations of seismicity parameters (e.g., a bias of up to 42% in the “b” parameter of the Gutenberg–Richter law). To address this issue, we compiled a homogenous earthquake catalog consisting of 39,977 events during the 1513–2016 period and accounted for site-specific local effects by developing site-specific scaling relationships between different measures of magnitude (e.g., mb, Ms, MD) and moment magnitude (Mw). The study area was subdivided into 15 seismogenic zones, accounting for site-specific seismicity patterns. The parameters “a” and “b” of the Gutenberg–Richter law were estimated for each zone based on independent earthquake events. The PSHA was performed using a standard logic tree approach, which allowed us to systematically take into account the model-based uncertainty and its influence on the estimated ground motion parameters. Uniform hazard spectra for return periods of 475 and 2475 years were estimated for peak ground accelerations and spectral accelerations at 0.2 s and 1.0 s to meet the definitions of seismic hazards provided by the International Building Code (IBC, International Code Council [ICC], 2009). This study is expected to provide a basis for design maps for building codes and emergency planning.