<p>Female fertility declines dramatically with age, primarily due to the loss of oocyte number and quality. This physiological event leads to ovarian dysfunction and infertility, irregular cycles and ultimately menopause. Despite its significance, the factors that underlie the natural process of age-related follicle loss, or those that promote premature ovarian aging, remain unknown. Here we show that low levels of chronic inflammation in mice lacking the nuclear factor kappa B transcription factor NF-ĸB1 (<i>Nfkb1</i>^{<i>−/−</i>}) coincide with accelerated depletion of the ovarian reserve, characteristic of premature ovarian aging. While <i>Nfkb1</i>^{<i>−/−</i>} mice enter adult life with normal numbers of primordial follicles, as females age, the primordial follicle pool is depleted more rapidly than in age-matched wild-type controls. Similarly, mice hemizygous for <i>Nfkb1</i> (<i>Nfkb1</i>^±) also exhibit an early loss of the ovarian reserve and a decrease in the number of corpora lutea, consistent with reduced ovulation. Loss of NF-ĸB1 was accompanied by elevated serum cytokine and intra-ovarian inflammatory levels. Overt ovarian fibrosis was not observed in aging <i>Nfkb1</i>^{<i>−/−</i>} mice, indicating that fibrosis may not the mechanism underlying premature follicle depletion. Collectively, these data suggest that loss of NF-ĸB1 and chronic low-grade inflammation may accelerate the age-associated depletion of follicles, leading to early loss of fertility and premature menopause.</p>