Sustained positive affect may decrease vulnerability to upper respiratory infections in cats admitted to a shelter. Incidence of upper respiratory infections was examined in cats rated as Content upon admission to an animal shelter when provided with or without treatment to sustain contentment. Ninety-six cats rated as Content upon admission were provided with either human interaction, including petting, playing, and grooming, in four 10min sessions/d for 10 days or were exposed to a control treatment of a human standing in front of the cage with eyes averted for the same period. Changes in emotional state and mucosal immune responses were measured daily in treated and control groups. Infectious status was determined upon admission and on days 4 and 10 using combined conjunctival and oropharyngeal swab specimens tested by quantitative real-time PCR for feline herpes virus type 1, feline calicivirus, Mycoplasma felis, Chlamydophila felis, and Bordetella bronchiseptica. The onset of upper respiratory disease (URD) was determined by veterinary staff based on clinical signs, including ocular or nasal discharge. Treated cats were more likely to remain Content (Incident Rate Ratio [IRR]:1.13, Confidence Interval: 0.98-1.30, P <0.0001) and less likely to be rated as Anxious or Frustrated than Control cats over a 10 day period (IRR: 0.61, 95% CI: 0.42-0.88, P =0.007). Feline secretory IgA (S-IgA) quantified in faeces by ELISA techniques, was greater for Treated than Control cats (1451 Vs 846μg/g). Within the Treatment group, S-IgA was greater for cats that sustained Contentment throughout the study period compared to cats that became Anxious or Frustrated (1846 Vs 1394μg/g). An increasing proportion of Control than Treated cats shed pathogens over time (Control 22%, 36%, 61%; Treated 35%, 26%, 32% on d 1, 4 and 10, respectively; P =0.006). Control cats were more likely to develop URD than Treated cats (HR 2.9, CI: 1.30-6.67, P =0.01). Cats that responded positively to Treatment had a lower incidence of URD than negative responders (P =0.02). We conclude that the provision of human interaction treatments to shelter cats can facilitate sustained contentment, enhance secretion of S-IgA, and reduce incidence of URD.