Previous research has shown that both experimentally-induced and naturally occurring upper respiratory tract illnesses (URTIs) influence mood and mental functioning. None of the previous studies of naturally occurring colds has conducted appropriate virological assays to determine the nature of the infecting agent. This is an essential methodological step in studies of malaise associated with URTIs. The aim of this research was to investigate the effects of naturally occurring colds on mood and objective measures of performance. This was done by first conducting a cross-sectional comparison of 37 healthy people and 158 volunteers with colds and then a longitudinal study in which 100 volunteers developed colds and 87 remained healthy. Virological techniques were used to identify infecting agents and comparisons made across the different groups. The results showed that having a cold was associated with reduced alertness and slowed reaction times. These effects were observed both for colds where the infecting virus was identified and those where it was not. Similar effects were obtained for both rhinovirus and coronavirus colds. One may conclude that upper respiratory tract illnesses lead to a reduction in subjective alertness and impaired psychomotor functioning. This was true for both illnesses where the infecting agent was identified and for those clinical illnesses where no virus was detected. It is now important to identify the mechanisms linking infection and illness with the behavioural changes. Similarly, the impact of these effects on real-life activities such as driving needs examining. Finally, methods of treatment need to be developed which not only treat the local symptoms of the illnesses but remove the negative mood and the performance impairments.