Feline interstitial cystitis (FIC) is a chronic pain syndrome of domestic cats. Cats with FIC have chronic, recurrent lower urinary tract signs (LUTS) and other comorbid disorders that are exacerbated by stressors. The aim of this study was to evaluate behavioral and physiological responses of healthy cats and cats diagnosed with FIC after exposure to a five day stressor. Ten healthy cats and 18 cats with FIC were housed at The Ohio State University Veterinary Medical Center (OSUVMC) vivarium. All cats were housed in enriched cages for at least one year prior to the experiment. Cats had daily play time and socialization outside of the cage, food treats and auditory enrichment. The daily husbandry schedule was maintained at a consistent time of day and cats were cared for by two familiar caretakers. During the test days, cats were exposed to multiple unpredictable stressors which included exposure to multiple unfamiliar caretakers, an inconsistent husbandry schedule, and discontinuation of play time, socialization, food treats, and auditory enrichment. Sickness behaviors (SB), including vomiting, diarrhea, anorexia or decreased food and water intake, fever, lethargy, somnolence, enhanced pain-like behaviors, decreased general activity, body care activities (grooming), and social interactions, were recorded daily. Blood samples were collected in the morning, before and after the stress period, for measurement of serum cortisol concentration, leukocytes, lymphocytes, neutrophils, neutrophil:lymphocyte (N:L) ratio and mRNA for the cytokines interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Overall, the short term stressors led to a significant increase in SB in both healthy cats and cats with FIC, whereas lymphopenia and N:L changes occurred only in FIC cats. Daily monitoring of cats for SB may be a noninvasive and reliable way to assess stress responses and overall welfare of cats housed in cages.