Experimental and epidemiological studies suggested that exposure to lead (Pb) may influence the hypothalamic-pituitary-adrenal (HPA) axis. However, previous studies have yielded mixed results. We evaluated changes in basal salivary cortisol levels and acute cortisol responsivity to psychological stress in relation with blood Pb levels (BPb), in Caucasian individuals 50–67 years of age. Data were collected through the Study of Genetics, Stress and Cognitive Development (2004–2006). Diurnal basal and stress-reactive salivary cortisol levels were collected and BPb levels were determined using inductively coupled plasma mass spectroscopy. A total of 65 participants were included in the current study. General linear mixed models were used to assess the association between BPb level and change in cortisol secretion over time, for diurnal basal pattern and stress-reactive pattern, respectively. The geometric mean BPb was 2.70 μg/dL (± 1.44) and two exposure groups were created based on the median value of 2.48 μg/dL. No difference in geometric mean of salivary cortisol (μg/dL) at awakening was observed between High and Low BPb groups (0.23 (± 0.11) vs 0.20 (± 0.11), p = 0.36). The overall pattern of change in both diurnal basal (from the awakening to bedtime) and reactive salivary cortisol (during the stress induction protocol) did not differ between groups. In these middle-aged and older adults, we concluded that Pb exposure, within the range observed in the current study, was associated with neither diurnal nor stress-reactive cortisol secretion. Further investigation with larger datasets are needed to confirm our observations.