Observational and experimentally induced infection studies show that upper respiratory tract infections (URTI) affect mood and cognition. This study tested the effects of naturally occurring URTI on cognition, mood and emotional processing, using a prospective design, with a broader array of tests than previous research, and with well matched control participants. Eighty participants (42 younger, M age 20.3 years; 38 older, M age 64.3 years) underwent neuropsychological assessment at baseline. Once a participant had URTI symptoms, s/he and a healthy, matched participant were retested. The Cognitive Drug Research computerised assessment battery was used to assess Power and Continuity of Attention, Quality of Episodic and Working Memory, Speed of Memory, and mood. Additionally, emotional processing was measured on matching of emotionally-negative faces with faces and faces with labels. Forty-two of 80 participants were matched (21 well, 21 ill). Well participants improved in Speed of Memory and face–label reaction time. Despite a lack of fever, ill participants demonstrated significantly smaller improvements. Older participants reported feeling less alert if ill, and less stressed if well, than at baseline. All ill participants reported less contentment than at baseline than well participants. Severity of URTI symptoms correlated with changes in Speed of Memory and mood. Even without fever, infectious disease produces large disturbances in speed of cognitive processing, particularly that reflecting retrieval from memory, and these effects are more marked in older participants. URTIs also affect mood. Future studies need to examine the role of inflammatory molecules and the brain regions implicated in mediating these findings.