Ruth Willmarth wakes one hot July night to a cacophony of drums, high-pitched warbling, and the bellowing of cows. Her lover, Colm, has invited his distant cousin, Darren, to fill in as herdsman on her Vermont farm, and Darren has brought along his extended family of volatile Irish Travellers. Among the crowd are Darren's estranged brother, Ritchie, and his beautiful but exhausted girlfriend, Nola, who has recently undergone brain surgery in a Toronto hospital. Now the hospital is seeking recent patients who might be infected with the human form of the fatal Mad Cow.

Almost as soon as they arrive, Ritchie is found in the local swamp, strangled with the reins of a neighbor's "darling" Morgan mare, and Nola disappears, prompting a widespread search for a "plague-carrying female killer."

The troubles pile up on Ruth's barn step when calves on the New York farm where Darren, Ritchie, and Nola worked contract Mad Cow. The Feds want to slaughter the two calves Ruth bought from that farmer and quarantine, without proof, her whole beloved herd.

Harassed by reporters, the Feds, and paranoid townsfolk, Ruth is trying to hold herself together. But when her kooky sister-in-law arrives with a van load of women to reenact an ancient Black Plague dance and demand that the "gypsies" leave, she breaks down. It takes a fire in the Travellers' trailer to bring her out of her funk. Desperate to find Nola and ascertain her state of health, Ruth springs into action.

Told in a variety of offbeat voices, and with a vibrant sense of place, Mad Cow Nightmare is the sometimes humorous, sometimes heartbreaking, but always suspenseful story of a fiercely independent woman who throws herself against hate and superstition in order to save farm, family, and a dying way of life.