Reiko Natsume was Takashi Natsume's maternal grandmother, possessing immense spiritual power that let her see and battle yokai. This gift caused humans to ostracize her as a bringer of misfortune, driving her to seek company primarily among yokai, though these interactions were often fraught. Her frustration and loneliness manifested in challenging yokai to duels; defeated spirits surrendered their names to her "Book of Friends," a ledger granting control over them. Despite her formidable reputation, her actions stemmed from isolation, not malice. She occasionally showed unexpected kindness, like exorcising a troublesome spirit from young Shigeru Fujiwara's home or returning a stolen doll to a human child—though the latter act was mistaken for theft.

Physically, she closely resembled her grandson Takashi, featuring long silver hair and pale green eyes in the manga, or ash-blonde hair with amber eyes in the anime. She typically wore a sailor-style school uniform, often torn or dirtied due to human aggression, including children throwing rocks at her. Her expression frequently bore a faint, enigmatic smile masking her true feelings.

Reiko's background is largely undefined. Likely orphaned or passed among relatives, mirroring Takashi's early life, she had a brief relationship with an unidentified man, resulting in the birth of her daughter out of wedlock. The father's absence fueled community rumors about her instability, deepening her marginalization. Her daughter, Takashi's mother, did not inherit her spiritual abilities and was quiet and ordinary. Reiko raised her daughter alone but died young, leaving few memories. Her death occurred "under a tree," with undisclosed circumstances.

Her personality blended abrasiveness with vulnerability. While she bullied humans and yokai alike, she also formed genuine connections with spirits like Santo, Gomochi, and Hidika, who awaited her return despite broken promises. Her forgetfulness—whether from neglect or her premature death—left many yokai waiting decades for resolutions her grandson later addressed. Poor social skills, partly from isolation, led her to feign apathy toward others' perceptions. Moments of empathy surfaced, like her bond with the terminally ill Soko Morinaga, who inspired her to formalize duels with yokai, inadvertently creating the Book of Friends.

Key relationships defined her fragmented life. The powerful yokai Madara (Nyanko-sensei) shared a complex bond with her; he could mimic her appearance and mannerisms and later acknowledged her as one of the few humans he respected, suggesting mutual regard. Other significant connections included Kibune, whom she freed from a forced marriage contract; Hinoe, whom she tricked into guiding her from a forest; and Soranome, the first spirit whose name she claimed. Her brief encounter with young Shigeru Fujiwara ended abruptly after property damage during the Karime exorcism, though Shigeru later forgot her identity.

Reiko's legacy centers on the Book of Friends, created to bind spirits but never used for control. Her forgetfulness left countless yokai awaiting her return, creating unresolved conflicts inherited by her grandson. These spirits often mistook Takashi for Reiko, seeking vengeance or fulfillment of old promises. Her life paralleled Takashi's struggles with alienation, though marked by greater isolation and fewer human connections. Her story underscores themes of misunderstood intentions and the search for belonging, resonating through Takashi's efforts to reconcile her past.