A foundational issue in firearms policy has been whether the type of weapon used in an assault affects the likelihood of death. To determine whether the likelihood of death from gunshot wounds inflicted in criminal assaults is associated with the power of the assailant's firearm as indicated by its caliber. Cross-sectional study with multivariate analysis of data on shooting cases extracted by the authors from police investigation files for assaults that took place in Boston, Massachusetts, between January 1, 2010, and December 31, 2014. These data were analyzed between October 1, 2017, and February 18, 2018. In all cases the victim sustained 1 or more gunshot wounds in circumstances that the Boston Police Department deemed criminal. The working sample included all 221 gun homicides and a stratified random sample of 300 nonfatal cases drawn from the 1012 that occurred during the 5-year period. Seven nonfatal cases were omitted because they had been misclassified. The primary source of variation was the caliber of the firearm used to shoot the victim. Whether the victim died from the gunshot wound(s). The final sample of 511 gunshot victims and survivors (n = 220 fatal; n = 291 nonfatal) was predominantly male (n = 470 [92.2%]), black (n = 413 [80.8%]) or Hispanic (n = 69 [13.5%]), and young (mean [SD] age, 26.8 [9.4] years). Police investigations determined firearm caliber in 184 nonfatal cases (63.2%) and 183 fatal cases (83.2%). These 367 cases were divided into 3 groups by caliber: small (.22, .25, and .32), medium (.38, .380, and 9 mm), or large (.357 magnum, .40, .44 magnum, .45, 10 mm, and 7.62 × 39 mm). Firearm caliber had no systematic association with the number of wounds, the location of wounds, circumstances of the assault, or victim characteristics, as demonstrated by χ2 tests of each cluster of variables and by a comprehensive multinomial logit analysis. A logit analysis of the likelihood of death found that compared with small-caliber cases, medium caliber had an odds ratio of 2.25 (95% CI, 1.37-3.70; P = .001) and large caliber had an odds ratio of 4.54 (95% CI, 2.37-8.70; P < .001). Based on a simulation using the logit equation, replacing the medium- and large-caliber guns with small-caliber guns would have reduced gun homicides by 39.5%. Firearms caliber was associated with the likelihood of death from gunshot wounds in criminal assault. Shootings with larger-caliber handguns were more deadly but no more sustained or accurate than shootings with smaller-caliber handguns. This conclusion is of direct relevance to the design of gun policy.