The impact of heat waves and cold spells on mortality has become a major public health problem worldwide, especially among older adults living in low- to middle-income countries. This study aimed to investigate the effects of heat waves and cold spells under different definitions on cause-specific mortality among people aged 65 years and over in Sao Paulo from 2006 to 2015. A quasi-Poisson generalized linear model with a distributed lag model was used to investigate the association between cause-specific mortality and extreme air temperature events. To evaluate the effects of the intensity under different durations, we considered 12 heat wave and nine cold spell definitions. Our results showed an increase in cause-specific deaths related to heat waves and cold spells under several definitions. The highest risk of death related to heat waves was identified mostly at higher temperature thresholds with longer events. We verified that men were more vulnerable to die from an ischemic stroke on heat waves and cold spells days than women, while women presented a higher risk of dying from ischemic heart diseases during cold spells and tended to have a higher risk of chronic obstructive pulmonary disease than men. Identification of heat wave- and cold spell-related mortality is important for the development and promotion of public health measures.