The purpose of the present study was to examine whether male painters reporting multiple chemical sensitivity (MCS) differ from their matched controls (male painters without such sensitivity) during controlled chamber challenges to singular and mixtures of odorous chemicals with respect to: (1) Subjective rating of symptoms (i.e., symptoms related to central nervous system (CNS) and symptoms related to irritation) and sensations of smell elicited by low-level chemical exposures. (2) Changes in serum prolactin and cortisol levels, changes in nasal cavity and eye redness as a result of the various exposures. Moreover, background assessments were made regarding mental well-being, sense of coherence (SOC) as well as state of anxiety and depression in both groups. The MCS and control group consisted of 14 and 15 male painters respectively. Regarding background assessments of mental well-being, anxiety, depression and SOC, statistically significant differences were obtained between painters with MCS and their controls. During the controlled chamber challenges, neither difference regarding sensations of smell nor development of CNS related symptoms were seen between MCS and control group. In contrast, subjective rating of symptoms related to irritation (i.e., eyes, nose, throat, skin, and breathing difficulties) was significant higher in subjects with MCS. No differences between the groups as a result of the different exposures were seen concerning nasal cavity, eye redness and serum cortisol levels. However, a trend (P = 0.056) between the groups was measured regarding a decline of serum prolactin levels in the MCS group. This is a relatively small study with a limited number of volunteers; and no definitive conclusions can be drawn concerning the above findings. But it is the first controlled challenge study that incorporates similarly exposed groups (painters) recruited from a community rather than from a clinical population.