Aims: The present study set out to investigate the relation of the high-density lipoprotein cholesterol (HDL-C) level to cognitive performance and its interplay with key markers of cognitive reserve in a large sample of older adults. Methods: We assessed tests of working memory, immediate and delayed cued recall in 701 older adults from Amazonas, Brazil. The HDL-C level was derived from fasting blood samples. In addition, we interviewed individuals on their education, past occupation, and cognitive leisure activity. Results: A critically low HDL-C level (<40 mg/dL) was significantly related to lower performance in working memory, immediate and delayed cued recall. Moderation analyses suggested that the relations of the HDL-C level to working memory and delayed cued recall were negligible in individuals with longer education, a higher cognitive level of the job, and greater engagement in cognitive leisure activity. Conclusion: Cognitive reserve accumulated during the life course may reduce the detrimental influences of a critically low HDL-C level on cognitive functioning in old age.