Having positive psychological well-being has been associated with serum high-density lipoprotein cholesterol (HDLC), but no longitudinal study to date has examined the association between Ikigai and serum HDLC. Therefore, we examined the association between Ikigai and change in serum HDLC over time using a cohort dataset spanning 2010-2018. The study included 471 men and 776 women aged 40-74years who underwent a cardiovascular examination in 2010 and were asked their levels of Ikigai. We combined "definitely yes" and "yes" as "with Ikigai" and recorded "a little" as "with a little Ikigai" and "no" as "without Ikigai". We measured serum HDLC using direct methods. The association between Ikigai and serum HDLC levels at baseline, and changes in this relationship during an eight-year period, were analyzed using linearmixed-effect models. At the baseline, relative to those without Ikigai, women with Ikigai had higher serum HDLC (baseline difference in those with a little Ikigai = 7.52mg/dl, 95% confidence interval [CI]: 1.12 to 13.9 and in those with Ikigai = 8.11mg/dl, 95% CI: 1.54 to 14.7). The difference in serum HDLC between women with and without Ikigai remained over the eight-year follow-up period. There were no similar Ikigai-associated differences in the serum HDLC of men. Women with Ikigai showed differences in serum HDLC that were observed at baseline and persisted over time.