This functional magnetic resonance imaging study investigates the effects of nicotine in a cued target detection task when changing cue reliability. Fifteen non-smoking volunteers were studied under placebo and nicotine (Nicorette polacrilex gum 1 and 2 mg). Validly and invalidly cued trials were arranged in blocks with high, middle and low cue reliability. Two effects of nicotine were investigated: its influence on i) parietal cortex activity underlying the processing of invalid vs. valid trials (i.e. validity effect) and ii) neural activity in the context of low, middle and high informative value of the cue (i.e. cue reliability effect). Nicotine did not affect behavioral performance. However, nicotine reduced the difference in the blood oxygenation level dependent (BOLD) signal between invalid and valid trials in the right intraparietal sulcus. The reduction of parietal activity in invalid trials was smaller in the low cue reliability condition. The same posterior parietal region exhibited a nicotinic modulation of BOLD activity in valid trials which was dependent on cue reliability: Nicotine specifically enhanced the neural activity during valid trials in the context of low cue reliability, i.e. when subjects are already in a state of low certainty. We speculate that the right intraparietal sulcus might be part of two networks working in parallel: one responsible for reorienting attention and the other for the cholinergic modulation of cue reliability. By reducing the use of the cue, nicotine modulates parietal activity related to reorienting attention in conditions with higher cue certainty. On the other hand, nicotine increases parietal activity in states of low certainty. This enhanced activation might influence brain regions, such as the posterior cingulate, directly involved in the processing of cue reliability.