Relative sensory irritation responses for Swiss-Webster mice exposed nose-only to mainstream tobacco smoke were evaluated for several cigarette types using a smoking regimen consisting of a 35-ml puff,  2 s in duration, taken once per minute. The degree of sensory irritation for each cigarette type was evaluated as the smoke concentration inducing a 50% reduction in breathing frequency. The smoke concentration inducing 50% respiratory depression is called the RD₅₀ value. Study findings suggest that mainstream tobacco smoke from the Eclipse cigarette, which primarily heats rather than burns tobacco, yielded an RD₅₀ that was significantly higher (approximately twofold) than a tobacco-burning leading ultralight or the 2R4F or 1R5F reference cigarettes. This is indicative of reduced upper airways irritation by Eclipse that may be due to its distinct design. Study findings suggest that the irritating nature of mainstream tobacco smoke from different cigarette types can be evaluated effectively in terms of smoke concentration using the relative sensory irritation assessment. These findings constitute the first report about use of the RD₅₀ sensory irritation response during comparative evaluations of mainstream tobacco smoke.